Respir Care Clin 9 (2003) 437–456
Management of acidosis during
lung-protective ventilation in acute
respiratory distress syndrome
Richard H. Kallet, MS, RRT, FAARCa,b,*,
Kathleen Liu, MDc, Julin Tang, MD, MSc
a
Critical Care Division, Department of Anesthesia, University of California
San Francisco at San Francisco General Hospital, 1001 Potrero Avenue,
San Francisco, CA 94110, USA
b
Cardiovascular Research Institute, 505 Parnassus Avenue, Box 0130,
San Francisco, CA 94143-0130, USA
c
Department of Anesthesia, University of California San Francisco,
San Francisco, CA 94110, USA
Acidosis is a frequent complication in patients who have acute
respiratory distress syndrome (ARDS). Traditionally, mechanical hyperventilation is used to return pH to a safe level, and the rapidity with which
pH can be corrected makes respiratory compensation appealing. In ARDS,
however, the functional lung size is markedly reduced and susceptible to
stretch-related injury. High levels of minute ventilation (V_ ) are needed to
correct pH and often require relatively large tidal volumes (VT) and high
airway pressures. The remaining healthy lung tissue is exposed to
extraordinarily high stresses that eventually perpetuate lung injury [1] and
increase mortality risk [2–4]. Yet, if left untreated, severe acidosis may
compromise normal cellular function and contribute to hemodynamic
instability [5]. Thus, clinicians may find themselves in a quandary regarding
when and how to treat acidosis and to what degree lung-protective
ventilation (LPV) can be prudently modified to obtain a safe pH. This article
reviews the rationale and principles of treating acidosis and is intended as
a practical guide to the management of acidosis under highly circumspect
conditions.
* Corresponding author. Department of Anesthesia, San Francisco General Hospital,
NH:GA-2, 1001 Potrero Avenue, San Francisco, CA 94110.
E-mail address: [email protected] (R.H. Kallet).
1078-5337/03/$ - see front matter Ó 2003 Elsevier Inc. All rights reserved.
doi:10.1016/S1078-5337(03)00034-0
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R.H. Kallet et al / Respir Care Clin 9 (2003) 437–456
Acid–base balance and buffering
Hydrogen ions (H+) are the byproduct of metabolism; the largest source
is attributable to CO2 production (approximately 15,000 mEq/day) [6,7].
Another 70 mEq/day of nonvolatile acids are produced from catabolism of
food and cellular processes [6]. In contrast, biologic processes function
within an H+ concentration range of only 140 nEq/L, and the arterial H+ is
regulated between 36 and 43 nEq/L, producing a pH of 7.36 to 7.44 [6].
Arterial pH is used as a gross reflection of the intracellular environment,
where the pH is 7.0 to 7.30 depending on tissue-specific chemical and
physiologic processes [7].
Maintenance of normal intracellular pH is crucial because of the vital
role proteins perform in the regulatory and structural function of cells. Most
proteins contain charged moieties, and even miniscule intracellular
disturbances in electrical charge can markedly alter cellular function.
Stability of both intra- and extracellular pH requires large buffer reserves.
The extracellular buffering systems include the carbonic acid–bicarbonate
system, along with hemoglobin, plasma proteins, and creatinine [6,8].
Intracellular buffering systems include proteins, polypeptides, and phosphate [6,8].
Definition and consequences of severe acidosis
Acidosis is defined as an arterial pH of less than 7.35. (The term acidosis
actually refers to a physiologic state in which the body fluids are acidified.
This condition often must be inferred from pH measured in the arterial
blood. The more precise term to describe an arterial pH below 7.35 is
acidemia. To avoid awkwardness, the term acidosis is retained, with the
understanding that much of the discussion focuses on the condition of
acidemia.) The threshold for severe acidosis is considered to be an arterial
pH below 7.20 [5,9]. The adverse consequences of acidosis occur
independently of whether acidosis is respiratory or metabolic in origin [5].
Severe acidosis causes increased metabolism, insulin resistance, inhibited
anaerobic glycolysis, reduced ATP synthesis, increased protein degradation,
and hyperkalemia [5]. Cardiovascular impairment is the major clinical
concern, because severe acidosis can cause reduced cardiac contractility,
arteriolar dilation, venoconstriction with centralization of circulating blood
volume, and increased pulmonary vascular resistance. These effects result in
decreased cardiac output and decreased arterial blood pressure with reduced
renal and hepatic perfusion [5,10]. In addition, severe acidosis sensitizes the
heart to reentrant arrhythmias and lowers the threshold to ventricular
fibrillation [5]. When the arterial pH is greater than 7.20, the cardiovascular
effects of acidosis are mild because of the activity of the compensatory
sympathetic nervous system [9]. The direct depressive effects of acidosis on
cardiovascular function become more dominant as the pH falls below 7.20
R.H. Kallet et al / Respir Care Clin 9 (2003) 437–456
439
[5], with responsiveness to catecholamines substantially diminished at a pH
below 7.10 [9]. Therefore, the clinical objective for treating acidosis in
patients with ARDS is not to normalize arterial pH but to return it to
a relatively safe level ( 7.20) that supports optimal cardiovascular function
[5,9].
Classification of acidosis
An essential principle governing extracellular acid-base physiology is
described by the Henderson-Hasselbalch equation in which pH is determined by the relationship between the bicarbonate concentration
(HCO3) and the partial pressure of arterial carbon dioxide (PaCO2) as
a reflection of carbonic acid concentration:
pH ¼ pK þ log ðHCO3 4 ½0:03 Paco2 Þ
As described by this equation, pH is directly proportional to HCO3 and
inversely proportional to PaCO2, so all acidosis can be categorized as
emanating primarily from either a rise in PaCO2 (respiratory) or a reduction
in HCO3 (metabolic). In reality, in critically ill patients the source of
acidosis often is mixed, and compensatory mechanisms may be engaged.
Respiratory acidosis
The relationship between PaCO2 and plasma HCO3 can be used to assess
the respiratory component of acidosis. When the plasma HCO3 is normal,
an acute rise in PaCO2 of 10 mm Hg results in a 0.08-unit decrement in pH
(D pH = DPaCO2 0.008) and a corresponding 1 mEq/L-increase in the
plasma HCO3 (Table 1) [11]. The change in HCO3 reaches completion
within 10 minutes and has an acute upper compensation limit of 30 mEq/L
[11,12]. As hypercapnia becomes chronic and renal compensation leads to
conservation of HCO3, an acute rise of 10 mm Hg in PaCO2 produces
a 0.03-unit decrement in pH (D pH = DPaCO2 0.003), with a corresponding 3.5-mEq/L increase in the plasma HCO3 [11]. Changes in HCO3
related to renal compensation begin within 12 to 24 hours and reach
completion by 72 to 96 hours, with an upper compensation limit of 45 mEq/
L [11,12]. When respiratory acidosis coincides with a metabolic acidosis, the
rise in plasma HCO3 in response to increasing PaCO2 is less than predicted
[11], and, in the presence of renal disease, normal compensatory mechanisms
may fail entirely.
Metabolic acidosis
Metabolic acidosis is produced either by the addition of nonvolatile acids
or through the loss of HCO3 or other buffers. It is characterized by
a plasma HCO3 of less than 22 mEq/L, because almost 90% of metabolic
acid buffering is achieved through the consumption of bicarbonate [13]. For
PaCO2 ¼ 1.5 (HCO3) þ 8
(Naþ þ Kþ) (HCO3 þ Cl)
# 1 g/dL Alb ¼ # 2.5–3 mEq/L AG
Rule
PaCO2 50 mm Hg
" PaCO2 of 10 ¼ # pH of 0.08
" PaCO2 of 10 ¼ " HCO3 of 1 mEq/L
" PaCO2 of 10 ¼ # pH of 0.03
" PaCO2 of 10 ¼ " HCO3 of 1–3.5 mEq/L
Plasma HCO3 < 22 mEq/L
# 1 mEq/L HCO3 ¼ # 1–3 mm Hg PaCO2
Gap acidosis > 18 mEq/L
Correction when Alb < 4 g/dL:
" AG 2.5–3 for every 1 g # Alb
10–15 mm Hg
45 mEq/L
30 mEq/L
Limits
Abbreviations: Alb, albumin; Cl, chloride; HCO3, plasma bicarbonate concentration; Kþ, potassium; Naþ, sodium; PaCO2, arterial carbon dioxide
tension.
Anion gap (AG)
Hypoalbuminemia
Metabolic acidosis
D pH ¼ D PaCO2 0.003
D pH ¼ D PaCO2 0.008
Respiratory acidosis
Acute
Chronic
Formula
Condition
Table 1
Clinical guidelines in interpreting acid–base changes
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441
every 1-mEq/L decrement in HCO3, PaCO2 decreases by 1 mm Hg,
a relationship that can be approximated by Winter’s formula [12,13]:
Paco2 ¼ 1:5ðHCO3 Þ þ 8
Respiratory compensation for metabolic acidosis is generally reached in
12 to 24 hours with a compensation limit in PaCO2 of approximately 10 to 15
mm Hg [12,13]. As in respiratory acidosis, deviation from the predicted
PaCO2–HCO3 relationship suggests mixed acidosis, limitations in pulmonary gas exchange capabilities, or a severe, rapidly worsening acidosis [13].
Renal correction of metabolic acidosis is slow, taking several days to reach
full adaptation, and is predicated on both normal extracellular volume and
renal function [13], conditions often absent in patients who have ARDS.
Full renal correction of metabolic acidosis requires that the source be
nonrenal and the total acid load less than 250 mEq/day [13].
Anion gap and metabolic acidosis
The addition of nonvolatile acids or a primary loss of HCO3 results in
metabolic acidosis. These subtypes of acidosis are differentiated by the
serum electrolyte balance. The anion gap refers to the difference between the
sum of the serum sodium Na+ and potassium K+ concentrations minus
the sum of the serum chloride Cl and HCO3 concentrations. The normal
anion gap occurs because sulfate, phosphate, organic anions such as lactate,
and weak-acid proteins are not routinely measured, whereas there are few
unmeasured cations [14]. The anion gap provides a quick method of
determining whether a decrease in HCO3 is caused by a disruption in the
normal anion balance or by the presence an abnormal acid anion (Table 2).
For example, the loss of HCO3 because of severe intestinal fluid drainage
causes a compensatory increase in Cl, and the anion gap remains normal.
Alternatively, lactic acidosis causes the loss of bicarbonate without changing
Cl and results in an increased anion gap.
A normal anion gap is approximately 8 to 14 mEq/L but may range
between 5 and 18 mEq/L, because the value is analyzer-dependent and must
be established by each laboratory [12,15]. Also, some prefer to ignore K+ in
the calculation, yielding slightly smaller values [14]. Serum proteins are an
important determinant of the anion gap, so hypoalbuminemia, a common
finding in ARDS, significantly lowers the anion gap [12,14]. As a rule, for
every 1-g reduction in serum albumin below 4 g/dL, the anion gap is
corrected upwards by 2.5 to 3 mEq/L [12,14].
Permissive hypercapnia and the nonbuffer management of
respiratory acidosis
The goals of LPV are to maintain the end-inspiratory plateau pressure
(Pplat) at or below 30 cm H2O, a Pplat–positive end-expiratory pressure
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Table 2
Causes of metabolic acidosis classified by normal and increased anion gap
Normal Anion Gap Acidosis
(Gap 18 mEq/L)
Increased Anion Gap Acidosis
(Gap > 18 mEq/L)
Gastrointestinal Fluid Lossesa
Renal HCO3 losses
Ileal bladder
Proximal RTA
Diamox-induced
Decreased renal Hþ secretion
Distal RTA
Type IV RTA
Early renal failure
Hyperalimentaion-related
Resuscitation-relatedb
Lactic Acidosis
Uremic Acidosis
Salicylate Poisoning
Methyl Alcohol Poisoning
Ethylene Glycol
Paraldehyde-Related
Ketoacidosisc
INH Toxicity
Abbreviation: Cl, chloride; RTA, renal tubular acidosis.
a
Pancreatic, bile, and small intestinal fluid all contain substantial amounts of bicarbonate
so that large volume losses through diarrhea or fistulas can cause a nongap metabolic acidosis.
b
In the critical care setting, an excessive chloride load typically results from aggressive fluid
resuscitation with normal saline but also has been associated with hetastarch administration.
c
This category includes ketoacidosis related to diabetes, alcohol abuse, and starvation.
(PEEP) difference of less than 20 cm H2O, and a VT between 4 and 6 mL/kg
predicted body weight (PBW). To prevent acute respiratory acidosis, VE is
maintained by increasing the respiratory rate in proportion to the reduction
in VT (ie, VE 4 target VT = target respiratory rate so that 14 L/minute 4
0.4 L/breath = 35 breaths/minute). High respiratory rates during LPV can
cause dynamic hyperinflation resulting in intrinsic PEEP and increased
dead-space ventilation [16,17]. This condition seems to be problematic when
the inspiratory-to-expiratory ratio is not decreased to compensate for the
reduction in total cycle time so that expiratory time approaches 1 second.
When the respiratory rate needed to maintain VE becomes unreasonable
(perhaps > 35–40 breaths/minute), several practical steps may ameliorate
acidosis and maintain a reasonable degree of LPV. Respiratory acidosis can
be managed relatively easily by allowing the PaCO2 to rise slowly over several
hours [18,19]. Therefore, the PaCO2 should increase by 10 mm Hg/hour or
less [20]. For example, in the National Institutes of Health (NIH) ARDS
Network protocol [3] the VT was reduced by 1 mL/kg over a 2- to 3-hour
period. For a patient with a PBW of 66 kg, this rate would amount to VT
reduction of 0.3 to 0.5 mL/kg/hour (20 to 33 mL/hour). Using the NIH
ARDS Network maximum rate of 35,VE would be reduced by 0.7 to 1.1 L/
minute/hour. In acute respiratory failure, a PaCO2 of 80 mm Hg or less, with
an arterial pH of 7.15 or higher, generally is well tolerated if hypoxemia and
hypovolemia are not present [20].
During LPV, CO2 excretion can be enhanced by removing extraneous
tubing between the endotracheal tube and the circuit Y-adapter to reduce
mechanical dead-space. In particular, heat and moisture exchangers (HME)
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443
are problematic [21,22]. Lung-protective ventilation in adults often requires
a VT of 400 mL or less, so that HMEs (with a volume of approximately 100
mL) can cause a substantial increase in mechanical dead-space. Hurni et al
[21] found that PaCO2 decreased by 37 to 42 mm Hg with HME removal,
whereas Prin et al [22] found that replacing an HME with a heated
humidifier reduced PaCO2 by 11 mm Hg and increased pH from 7.20 to 7.26
without adjusting VE.
Alternatively, PaCO2 can be reduced during LPV with tracheal gas
insufflation (TGI) to wash out CO2-laden gas from the airways during
expiration [23,24]. A TGI expiratory flow of 15 L/min can reduce PaCO2 by
more than 20 mm Hg and increase pH by 0.14 units [23,24]. Tracheal gas
insufflation, however, can increase Pplat [23]; therefore, applied PEEP must
be reduced to prevent the build up of intrinsic PEEP [24]. Increasing the
respiratory rate to the threshold of intrinsic PEEP and removing
mechanical dead-space has been shown to be as effective as TGI; but the
combination of TGI and these practical steps has an additive effect on CO2
excretion [24].
According to the Bohr equation, PaCO2 is directly proportional to CO2
minute production (V_ CO2) and inversely proportional to alveolar minute
ventilation [25]. Thus, for any VE, reducing VECO2 should decrease PaCO2.
Reduction of fever and control of caloric intake (and caloric substrate) can
be used to reduce either VE demand or PaCO2. As a rule, PaCO2 increases by
13% per 1 C rise in temperature above normal [25]. Manthous et al [26]
found that reducing mean temperature from 39.4 to 37.0 C over 3 hours in
patients who had respiratory failure reduced VECO2 by 20%. When caloric
intake exceeds resting energy expenditure by a factor of 1.5 to 2, VECO2
progressively increases, and hypercapnia is frequently the result, particularly when VE is constrained [27–29]. In particular, excess carbohydrate
administration increases VECO2 both by glycolysis and lipogenesis [27]. At
a fixed VE, there is lower VECO2 and less hypercapnic acidosis when glucose
is replaced by lipid [29].
Patient–ventilator asynchrony and acidosis during lung-protective ventilation
Traditionally, acidosis is buffered when it is severe enough to cause
hemodynamic instability. During LPV, however, the treatment threshold
may be lowered to protect the lungs and to lessen patient–ventilator
asynchrony. Lung-protective ventilation often requires a target VT less than
the VT demand of patients who have intact respiratory drive. This situation
presents an intractable management problem, because adjusting inspiratory
flow rate and trigger sensitivity to lessen patient work of breathing and
distress is particularly ineffective [30–32]. Adequate treatment of severe
asynchrony often requires high levels of sedation that may induce
hemodynamic instability or promote ventilator dependence [33]. Severe
asynchrony often requires use of paralytic agents, which has been associated
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with myopathies and prolonged ventilator dependence [34]. A recent study
found that during the NIH ARDS Network trial, both asynchrony and
inadequate sedation were significant barriers to achieving LPV [35].
It has been reported that ARDS patients manifesting signs of asynchrony
and distress during LPV had a lower pH and a higher base deficit [32]. These
patients could not reach VT goals despite optimization of inspiratory flow
rates and trigger sensitivity. Patients who had a base deficit greater than 5
mEq/L were twice as likely to develop asynchrony. Acidosis directly affects
ventilatory drive at an arterial pH below 7.30 [36]. Tidal volume usually
increases in response to acidosis [37], and this increase is a particular
characteristic of the response to metabolic acidosis (ie, Kussmaul breathing)
[13]. During unassisted breathing, a VT demand of 800 to 1300 mL is
common at a pH of 7.20 or less [37]. Constraining ventilator VT below
patient demand typically results in frequent double-triggered breaths (two
mechanically delivered breaths during one spontaneous effort) [30]. Thus,
a patient set at a VT of 6 mL/kg will actually receive a 12-mL/kg VT,
increasing the risk of barotrauma and ventilator-associated lung injury.
Once fully engaged, adaptive changes in respiratory drive may persist for
several days after the acidosis has been corrected [38]. Therefore, buffering
acidosis might facilitate the achievement of VT goals without increasing
sedation or use of paralytic agents.
Management of acidosis with alkali therapy
Primary respiratory acidosis and sodium bicarbonate
In general, treating primary respiratory acidosis with NaHCO3 is
discouraged [6,8,11,20,39]. Although several risks are associated with
NaHCO3 the most prominent concern is an acute worsening of intracellular
acidosis [6,8,11,20]. During LPV, NaHCO3 should never be administered as
a bolus. Approximately 10% to 15% of HCO3 immediately converts to CO2,
so that a typical 1-mEq/kg dose given rapidly results in approximately 200 mL
of CO2 (equivalent to 1 minute of CO2 production for an average-size adult)
[9]. Therefore, unless alveolar ventilation is doubled, respiratory acidosis will
worsen acutely. Therapy with NaHCO3 is discouraged during cardiopulmonary resuscitation, in part because the high dead-space fraction (0.60)
requires that total VE be increased by an additional factor of 2 to 4 to prevent
an acute worsening of acidosis [9]. Similarly, in early ARDS, the dead-space
fraction often is 0.60 or higher [40]. Unlike HCO3, the CO2 produced from
rapid NaHCO3 infusion readily diffuses across cell membranes, so the primary
effect is an acute worsening of intracellular acidosis. This worsening of
intracellular acidosis may produce a greater degree and more rapid onset of
myocardial depression during acute respiratory acidosis than may occur
during metabolic acidosis at the same pH [9].
R.H. Kallet et al / Respir Care Clin 9 (2003) 437–456
445
In addition, NaHCO3 therapy has limited efficacy in treating respiratory
acidosis. Up to 40% of NaHCO3 is lost rapidly in the urine [41]. More
importantly, the sensitivity of pH to HCO3 is inversely proportional to
PaCO2 [20], so that extraordinary amounts of NaHCO3 may be necessary to
produce small improvements in pH [20]. This therapy may result in
hypernatremia and excessive volume loading, which is generally undesirable
in patients with ARDS and pulmonary edema.
Administration of sodium bicarbonate in mixed acidosis
In general, NaHCO3 use in ARDS should be restricted to either metabolic
or mixed respiratory and metabolic acidosis. In these situations, NaHCO3
should be administered as a slow continuous infusion [20]. Usually 2 to 3
ampoules of NaHCO3 are added to 1 L of 5% dextrose, which is preferred over
normal saline to avoid administering an excessive sodium load. An ampoule of
NaHCO3 contains 50 mEq/50 mL. Before 100 to 150 mL of NaHCO3 is added,
100 to 150 mL of dextrose should be removed to make drug infusion rates
easier to calculate (ie, 10–15 mEq/100 mL versus 9.1–13 mEq/100 mL). Both
5% dextrose and normal saline are isotonic solutions that have an osmolality
of 252 and 306 mOsmols/L, respectively. Adding 2 to 3 ampoules of NaHCO3
to 5% dextrose produces a solution with an osmolality of approximately 452
to 552 mOsmol/L. The NaHCO3 infusion is usually titrated between 100 and
150 mL/hour, based on the estimated total extracellular base deficit. The
extracellular space is assumed to be 0.2 L/kg of lean body weight [9], but an
additional 0.1 L/kg is factored into the calculated extracellular base deficit.
Thus, total the NaHCO3 dose equals the base deficit (mEq/L) times 30% PBW
(kg). Arterial blood gas and electrolyte analysis should be monitored
frequently to assess and to titrate therapy.
Ventilation adjustments during sodium bicarbonate therapy
The effectiveness of treating metabolic acidosis with NaHCO3 is
predicated on the adequacy of alveolar ventilation. Part of the evaluation
for using NaHCO3 in ARDS is to examine the relationship between VE,
PaCO2, and Pplat. Based on recent clinical trials, intermediate levels of VE
are needed to produce normocarbia in early ARDS (11–13 L/minute)
[3,4,42]. This finding suggests that some flexibility in VE exists to
accommodate increases in CO2 production. When VE and Pplat are
relatively low, the respiratory rate (and to a lesser degree VT) is increased to
enhance the effectiveness of NaHCO3 without increasing the risk of lung
injury (Pplat 30 cm H2O). In the NIH ARDS Network trial, when
baseline VE was 18 L/minute or less, VT and Pplat goals were generally met
(6.3 0.9 mL kg and 25.6 5.7 cm H2O, respectively) [43].
The NIH ARDS Network low-VT protocol provides a guide for
balancing the risk/benefit ratio between LPV and the treatment of acidosis.
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In severe acidosis (pH < 7.15), the 30 cm H2O Pplat limit is temporarily
suspended (after the maximum respiratory rate of 35 has been reached), and
the VT is judiciously titrated upwards to a limit of 8 mL/kg to accommodate
NaHCO3 therapy until arterial pH equals 7.20 [44].
Sodium bicarbonate therapy in specific types of metabolic acidosis
The indications for NaHCO3 therapy depend on the cause of metabolic
acidosis and the circumstances in which it occurs. In diabetic ketoacidosis,
NaHCO3 therapy is no more effective than conventional therapy with
insulin, potassium, and normal saline [8], because most human studies found
NaHCO3 does not substantially decrease ketones or appreciably improve
arterial pH [8,10]. As discussed later, however, NaHCO3 given for uremic
acidosis, renal tubular acidosis, or acidosis related to gastrointestinal fluid
loss frequently results in improved pH [8]. Lactic acidosis probably is the
most common source of metabolic acidosis seen in ARDS.
Lactic acidosis
Lactic acidosis is defined as an arterial pH below 7.25 with a corresponding lactate level above 5 mmol/L [8]. Lactate levels above 9 mmol/L are
associated with a particularly high mortality rate (>75%) [8]. Type A, the
most common form of lactic acidosis, is associated with tissue hypoxia.
Type B lactic acidosis is caused by abnormal carbohydrate metabolism that
occurs with hepatic failure, ethanol poisoning, diabetes mellitus, malignancy, and some antiretroviral therapies [9,10,45]. Type B lactic acidosis is not
associated with the failure of aerobic metabolism, so there is a much lower
build-up of H+, and clinical treatment is less emergent [46].
The liver normally metabolizes 50% to 60% of lactate, and the kidneys
clear an additional 30% [6]. When the liver and kidneys are exposed to
acidosis or hypoxia, lactate clearance stops, and the liver actually begins to
produce lactate. Clinically, a sustained or acutely worsening lactic acidosis
usually indicates a simultaneous process of abnormal lactate production and
decreased clearance.
Effective therapy for type A lactic acidosis ultimately requires improvement in systemic oxygen delivery [46]. Because lactate production is high
during type A acidosis, NaHCO3 therapy is often impractical and at best
should be used as a bridge until oxygen delivery can be increased [46]. As
a rule, treatment with NaHCO3 is contraindicated when type A lactic
acidosis is associated with hypoxemia and cardiogenic shock [8,10]. In any
form of shock, NaHCO3 may worsen lactic acidosis because arterial pH can
improve more than intracellular pH, resulting in a leftward-shift in the
oxyhemoglobin dissociation curve that paradoxically makes less oxygen
available to the tissues [47].
Of particular relevance to ARDS management, most animal models of
hypoxemia-induced lactic acidosis have shown that NaHCO3 infusion
R.H. Kallet et al / Respir Care Clin 9 (2003) 437–456
447
increases mixed venous PCO2 and decreases both hepatic intracellular pH
(resulting in a reduced lactate clearance) and myocardial intracellular pH
(resulting in hemodynamic deterioration), leading to a progression in
acidosis [10]. In animals with lactic acidosis caused by hypovolemic or
hemorrhagic shock, NaHCO3 increases cardiac output and blood pressure
(ostensibly because of volume expansion) [10]. Compared with volume
resuscitation with normal saline, however, hemodynamic improvements
with NaHCO3 occurred with higher lactate levels and a delayed increase in
tissue PCO2 [47].
In prospective, clinical trials involving critically ill patients who had
sepsis-related lactic acidosis (pH of 7.16–7.22) [48,49], rapid NaHCO3
administration (1–2 mmol/kg over 15 minutes) significantly increased
arterial pH, PCO2, and plasma HCO3 but did not change hemodynamic
or oxygen-related variables compared with normal saline. In both of these
studies, oxygen saturation was 90% or greater, and arterial PCO2 was 35 mm
Hg at baseline. Most patients required vasopressor or inotropic support, but
the mean arterial blood pressure was above 60 mm Hg. These trials suggest
that NaHCO3 therapy may improve arterial pH during lactic acidosis when
ventilation is not impaired, arterial oxygenation is adequate, and shock has
been reversed.
Sodium dichloroacetate
Sodium dichloroacetate has been used to treat lactic acidosis because it
stimulates the oxidation of lactate to acetyl-coenzyme A [50]. Its use during
LPV is constrained by the fact that it also generates CO2 [50]. More
importantly, sodium dichloroacetate causes minimal improvement in pH
compared with placebo [50].
Carbicarb
Carbicarb, an equimolar solution of NaHCO3 and sodium carbonate, has
a higher pH than NaHCO3 (9.6 versus 8.0, respectively) and a lower PCO2 at
body temperature (3 versus 200 mm Hg, respectively) [51]. In animal studies
of metabolic acidosis, carbicarb improved arterial pH without increasing
PaCO2 compared with NaHCO3 [52–54]. Carbicarb also is an effective
intracellular buffer [53]. Unfortunately, there has been only one clinical trial
testing carbicarb. Leung et al [55] treated mild metabolic acidosis with
carbicarb and found it was no more effective than NaHCO3 in improving
arterial pH. Carbicarb is not currently available for clinical use in the
United States [44].
Tris-hydroxymethyl aminomethane
Tris-hydroxymethyl aminomethane (THAM) is an amino-alcohol (pH of
8.6) with substantially greater buffering capacity than NaHCO3 (pK, 7.8
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versus 6.1 respectively) and is an effective intracellular buffer [56].
Protonated THAM is excreted by the kidneys, so that CO2 production is
not raised [52]. By alkalinizing the urine, THAM increases renal excretion of
fixed acids [57]. Intracellular buffering occurs by two mechanisms. First,
THAM quickly distributes into a volume that approximates the extracellular space. Rapid intracellular buffering (particularly of the brain and
cardiac muscle) occurs by a reduction in capillary and interstitial PCO2 that
causes a swift egression of CO2 out of the cells [56]. Second, the
nonprotonated THAM fraction slowly penetrates the intracellular compartment [56].
Used as rescue therapy during permissive hypercapnia in ARDS
complicated by severe metabolic acidosis, THAM increased mean pH
(from 7.14 to 7.26) and decreased mean PaCO2 (from 63 to 50 mm Hg) at the
same level of VE [58]. A reduction in PCO2 following infusion of THAM has
been widely reported [59–63]. Tris-hydroxymethyl aminomethane directly
binds CO2 [63], and the reduction in PaCO2 seems to be dose dependent
[58,59]. A consideration that may be relevant during LPV is that THAM
acts as a respiratory depressant [56] primarily by reducing VT [60], and has
been shown to attenuate myocardial depression rapidly during permissive
hypercapnia in ARDS [64].
Tris-hydroxymethyl aminomethane is available as a 500 mL, 0.3 Msolution containing 150 mEq of buffer (Abbot Laboratories, Abbott Park,
IL). Acute intravenous infusion is based on correction of an acid load
exceeding the extracellular volume by 10%:
Total dose ðmEqÞ ¼ ð0:3 PBW in kgÞ base deficit ðmEq=LÞ
Between 25% and 50% of the total dose is given intravenously over 5 to
10 minutes as a loading dose; the remainder is administered over 1 hour [56].
Because THAM may cause rapid changes in glucose and potassium,
administration should not exceed 2 mmol/kg over 30 minutes or 5 mmol/kg
over 1 hour [56]. This administration rate translates into a 2- to 5-mEq/kg
restriction over 30 and 60 minutes, respectively. Tris-hydroxymethyl
aminomethane can be continuously infused at 0.5 to 1.0 mEq/kg/h for 4
to 10 hours [56]. In severe ARDS, the authors have used a continuous
infusion of 0.55 mEq/kg/hour over 39 hours [58], whereas Nahas et al [56]
used an infusion of 0.3 to 0.6 mEq/kg/hour over 10 days. In patients who
have normal creatinine clearance, the total THAM dose should not exceed
15 mEq/kg/day [56].
Tris-hydroxymethyl aminomethane is a hyperosmolar (389 mOsmols/L)
solution that causes a swift osmotic diuresis with electrolyte loss. Enhanced
excretion of Na+, K+, and Cl normally occurs. Plasma K+ levels usually
remain constant despite increased urinary losses, suggesting that a compensatory shift from the intracellular space occurs. Potassium shifts from the
intracellular compartment may cause hyperkalemia following rapid
correction of severe respiratory acidosis [56]. Patients who have renal
R.H. Kallet et al / Respir Care Clin 9 (2003) 437–456
449
insufficiency may be at more risk of hyperkalemia and should be monitored
closely. Supplementing a THAM solution with 30 mEq/L of NaCl and 5
mEq/L of KCl may compensate for urinary loss [56]. Diminished blood
glucose levels are linked to an increase in insulin release and a fall in plasma
phosphate when higher doses are rapidly infused (4 mEq/kg/hour). In severe
acidosis, the authors [58] have co-administered an ampoule of 50%
dextrose, because they have encountered situations in which the glucose
level fell precipitously from 125 to 25 mg/L.
The main contraindications to THAM are anuria, uremia, and pregnancy
(Category C). At very high doses (8.8 mmol/kg over 1 hour), THAM can
cause persistent hypotension and vomiting [56]. Tris-hydroxymethyl aminomethane should be administered through a central or a large antecubital
vein to avoid venospasm of smaller vessels.
Hyperchloremic metabolic acidosis
Hyperchloremic metabolic acidosis usually is not life threatening [14] and
is generally associated with three conditions: renal insufficiency or failure,
excessive HCO3 loss, or excessive Cl administration. Excessive HCO3
loss may be the result of gastrointestinal losses secondary to diarrhea or
renal tubular acidosis. In addition, surgical procedures including pancreatic/
biliary diversion and ureteral diversion may lead to HCO3 loss. Hyperchloremic metabolic acidosis also may occur following rapid correction of
hypocapnia (which leads to a compensatory metabolic acidosis) [65].
Excessive Cl administration typically results from aggressive fluid resuscitation with Cl-rich fluids. Each condition has a different therapeutic
approach.
Renal insufficiency, renal tubular acidosis, and renal failure
Acidification defects inherent to the kidney, known as renal tubular
acidosis, are rare but may occur in critically ill patients. Of particular note,
renal tubular acidosis may be induced by medications such amphotericin B,
gentamycin, and ifosphamide. There are three types of renal tubular
acidosis. In type I renal tubular acidosis, the distal nephron cannot secrete
normal amounts of H+, so the urine cannot be fully acidified (eg, a urine
pH > 6.0 coinciding with systemic acidosis) so that HCO3 is consumed [6].
Because renal HCO3 reclamation function is normal, type I renal tubular
acidosis usually can be treated with small amounts of buffer, either
NaHCO3 or a bicarbonate equivalent such as citrate (approximately 100
mEq/day) [6]. Proximal (type II) renal tubular acidosis results from the
inability to reclaim filtered HCO3 so that excessive amounts are lost in the
urine. Type II renal tubular acidosis is self limiting, and plasma HCO3
stabilizes at approximately 15 mEq/L. Treatment with potassium citrate
is more effective than NaHCO3 (which may lead to life-threatening
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R.H. Kallet et al / Respir Care Clin 9 (2003) 437–456
hypokalemia) [6]. Type IV renal tubular acidosis is attributable to a relative
aldosterone deficiency and is characterized by hyperkalemia. Treatment
consists of NaHCO3 administration, correction of hyperkalemia, and
consideration of mineralocorticoid therapy.
Moderate renal insufficiency (glomerular filtration rate of 20–50 mL/
minute) is characterized by a serum creatinine level of 4 mg/dL or less with
a modest decline in plasma HCO3[14]. Because organic anions can be
excreted, the anion gap remains normal, and the acidosis is hyperchloremic
in nature [66]. When renal failure becomes more severe (glomerular filtration
rate < 15 mL/minute), the kidneys can no longer excrete sulfates and
phosphates, so that an increased anion gap acidosis develops, and renal
replacement therapy becomes necessary [14]. The primary renal defect
leading to acidosis in this circumstance is impaired ammoniagenesis and
excretion.
Renal replacement therapy in the management of metabolic acidosis
Renal replacement therapies in the form of intermittent hemodialysis
(IHD) and continuous renal replacement therapy (CRRT) are frequently
used in the ICU for renal support when the glomerular filtration rate is 15
mL/minute or less [67]. There are several classic indications for dialysis
including metabolic acidosis, electrolyte abnormalities including hyperkalemia, volume overload, clinical signs of uremia (such as pericarditis), and
toxic ingestions. Unlike IHD, which is typically performed 3 to 5 times per
week for 3- to 4-hour sessions, CRRT is done continuously. In general,
CRRT is a more hemodynamically stable modality of therapy and, over
time, may allow greater fluid removal and improved clearance than possible
with IHD. In particular, CRRT can provide excellent long-term control of
metabolic acidosis and thereby play a helpful role during LPV [68].
Continuous renal replacement therapy may provide an additional supportive role in ARDS by clearing inflammatory mediators and removing
extravascular lung water [69].
Continuous renal replacement therapy is typically performed with
lactate-containing dialysate solutions (as opposed to HCO3-containing
solutions) that allow the addition of divalent cations such as magnesium and
calcium [70]. The lactate in these solutions is metabolized to HCO3 by the
liver. Thus, in patients who have severe hepatic dysfunction, these solutions
may not be tolerated and may result in a lactic acidosis that manifests as an
increasing anion gap following the initiation of CRRT. This problem can be
corrected with changes in the CRRT prescription. Continuous renal
replacement therapy is a means of stably and continuously correcting metabolic acidosis and allowing permissive hypercapnia.
Solutions containing HCO3-containing dialysate solutions have only
recently become commercially available. It remains unclear whether these
solutions offer any advantage over lactate-containing solutions in promoting
R.H. Kallet et al / Respir Care Clin 9 (2003) 437–456
451
hemodynamic stability, acid-base control, or improved mortality. With the
use of these solutions, approximately 60 to 80 mmol of HCO3 is delivered
per hour as part of an iso-osmolar solution [70]. Because the delivery of
HCO3 is relatively slow, it has been shown that use of these solutions
does not result in a significant increase in PaCO2 [71]. Finally, CRRT
typically leads to a reduction in body temperature, which, as mentioned
earlier, may help promote LPV in ARDS by reducing the PaCO2 for any
level of VE [72].
Excessive chloride administration
Metabolic acidosis related to excessive chloride administration is usually
associated with either aggressive fluid resuscitation or specific preparations
of total parenteral nutrition (TPN). In the latter situation, TPN solutions
containing synthetic L-amino acid preparations are believed to be responsible because of their higher concentrations of cationic amino acids [14].
This problem can be corrected by adding acetate to the TPN solution [14].
Aggressive volume expansion with normal saline can cause metabolic
acidosis and has been referred to as dilutional acidosis [73]. In theory,
plasma HCO3 is diluted by volume expansion, and renal HCO3 is lost in
the urine [74], but this explanation remains controversial. First, compelling
evidence suggests that high Cl, from excessive use of normal saline or
hetastarch, is a more likely cause of acidosis [74,75]. In fact, volume
expansion with either Ringer’s lactate solution or 5% albumin does not
cause metabolic acidosis [74,75]. Second, metabolic acidosis occurs even
when aggressive resuscitation with normal saline fails to expand intravascular volume [76].
Resuscitation-related metabolic acidosis may confuse the management of
patients who have traumatic or hemorrhagic shock. A worsening metabolic
acidosis in this context can be interpreted as persistent hypoperfusion,
requiring further volume expansion, thus exacerbating acidosis. When
ARDS complicates shock, volume overload exacerbates pulmonary edema,
worsens hypoxemia, and may negatively affect outcome [77–79]. Resuscitation-related metabolic acidosis should be suspected in the absence
of either an increasing anion gap or increasing lactate levels.
Because resuscitation-related metabolic acidosis seems to be an
extracellular phenomenon, its significance is unknown, and the need for
therapeutic intervention is questionable [80]. Although moderately severe
acidosis (pH of 7.15–7.20) can be induced with excessive normal saline
infusions [81], it may persist for only a few hours after fluid administration
[82]. Therefore, depending on the degree of acidosis and the severity of the
Cl excess, the acidosis may resolve without the need for buffer therapy, and
further volume expansion can be achieved with a low-Cl solution. If
buffering is necessary, treatment with NaHCO3 seems reasonable.
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R.H. Kallet et al / Respir Care Clin 9 (2003) 437–456
Summary
In ARDS, when acidosis complicates LPV, the goal of alkali therapy is to
maintain arterial pH at a safe level (7.20). A pure respiratory acidosis
generally does not require alkali therapy. If the Pplat is greater than 30 cm
H2O, and the respiratory rate equals the upper limit (35–40 breaths/minute),
then VE is slowly titrated down by approximately 1 L/hour, so that PaCO2
increases by 10 mm Hg/hour or less. Alkali therapy is indicated for either
a metabolic acidosis or a mixed acidosis. The choice of buffer is based on the
type of acidosis, cardiorespiratory status, and lung mechanics. Slow
infusions of NaHCO3 can be used to treat non-anion gap metabolic
acidosis and some forms of increased anion gap acidosis. Using NaHCO3 to
treat type A (hypoxia-related) lactic acidosis can be hazardous, particularly
under conditions of hypoxemia, inadequate circulation, and limited alveolar
ventilation. Under these circumstances, THAM is the preferable buffer
because it does not increase PaCO2 and is excreted by the kidneys. When
renal failure is present, CRRT is indicated to manage acidosis. When ARDS
is complicated by traumatic or hemorrhagic shock, overresuscitation with
Cl-rich solutions should be avoided to prevent metabolic acidosis.
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