Diagnosis and management of metabolic acidosis:

Jung et al. Ann. Intensive Care (2019) 9:92 https://doi.org/10.1186/s13613-019-0563-2

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guidelines from a French expert panel

Boris Jung1,2*, Mikaël Martinez3,4, Yann‐Erick Claessens5, Michaël Darmon6,7,8, Kada Klouche2,9, Alexandre Lautrette10,11, Jacques Levraut12,13, Eric Maury14,15,16, Mathieu Oberlin17, Nicolas Terzi18,19, Damien Viglino20,21, Youri Yordanov22,23,24, Pierre‐Géraud Claret25, Naïke Bigé14 , for the Société de Réanimation de Langue Française (SRLF) and the Société Française de Médecine d’Urgence (SFMU)

Abstract

Metabolic acidosis is a disorder frequently encountered in emergency medicine and intensive care medicine. As litera‐ ture has been enriched with new data concerning the management of metabolic acidosis, the French Intensive Care Society (Société de Réanimation de Langue Française [SRLF]) and the French Emergency Medicine Society (Société Française de Médecine d’Urgence [SFMU]) have developed formalized recommendations from experts using the GRADE methodology. The elds of diagnostic strategy, patient assessment, and referral and therapeutic management were addressed and 29 recommendations were made: 4 recommendations were strong (Grade 1), 10 were weak (Grade 2), and 15 were experts’ opinions. A strong agreement from voting participants was obtained for all recom‐ mendations. The application of Henderson–Hasselbalch and Stewart methods for the diagnosis of the metabolic acidosis mechanism is discussed and a diagnostic algorithm is proposed. The use of ketosis and venous and capillary lactatemia is also treated. The value of pH, lactatemia, and its kinetics for the referral of patients in pre‐hospital and emergency departments is considered. Finally, the modalities of insulin therapy during diabetic ketoacidosis, the indi‐ cations for sodium bicarbonate infusion and extra‐renal puri cation as well as the modalities of mechanical ventila‐ tion during severe metabolic acidosis are addressed in therapeutic management.

Keywords: Metabolic acidosis, Blood gas analysis, Anion gap, Hyperlactatemia, Ketoacidosis, Sodium bicarbonate, Renal replacement therapy

  

Introduction

e Henderson–Hasselbalch method de nes meta- bolic acidosis by the presence of an acid–base imbal- ance associated with a plasma bicarbonate concentration below 20 mmol/L. e association of this imbalance with decreased pH is called “acidemia,” which is often described as severe when the pH is equal to or below 7.20.

Metabolic acidosis is a frequent event in patients receiving emergency treatment or intensive care. Physi- cians have at their disposal numerous plasma and urine tests to characterize metabolic acidosis, determine its

*Correspondence: b‐jung@chu‐montpellier.fr
1 Département de Médecine Intensive et Réanimation, CHU Montpellier, 34000 Montpellier, France
Full list of author information is available at the end of the article

etiology, and refer patients. Acute metabolic acidosis may accompany various diseases and be associated with organ failure, in particular respiratory (increased ven- tilatory demand) and cardiovascular (arterial vasodila- tion, decreases in cardiac inotropism and cardiac output, ventricular arrythmia) [1–3]. e role of acute metabolic acidosis in these organ failures is mostly suggested by experimental studies in animals or in vitro, as few clinical studies in humans are available [1].

e last consensus conference on the “correction of metabolic acidosis in intensive care” was published in 1999 by the Société de Réanimation de Langue Fran- çaise (SRLF), with the participation of the Société Française d’Anesthésie et de Réanimation (SFAR), the Société Francophone d’Urgences Médicales (SFUM), the Groupe Francophone de Réanimation et Urgences Pédiatriques (GFRUP), Samu de France, the Société

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Française de Nutrition Entérale et Parentérale, and the Société de Néphrologie. Point-of-care testing has since grown and enables clinicians to access blood gas measurements very quickly, including in pre-hospital settings. In addition, new data on diagnosis and prog- nostic tools and the treatment of metabolic acidosis have enriched literature. is is why the SRLF and the Société Française de Médecine d’Urgence (SFMU) pro- pose these formal guidelines on the diagnosis and man- agement of metabolic acidosis. rough analysis of the level of evidence in the literature, the purpose of these guidelines is to specify the diagnostic strategy, referral of patients, and therapeutic management in pre-hos- pital settings, in the emergency room, and in intensive care.

Method

e guidelines were drawn up by a group of twelve experts convened by the SRLF and the SFMU. e group’s agenda was de ned beforehand. e organizing committee rst de ned the questions to be addressed with the coordinators and then designated the experts in charge of each question. e questions were formu- lated according to a Patient Intervention Comparison Outcome (PICO) format after a rst meeting of the expert group. Literature was analyzed and the guide- lines were formulated using Grade of Recommendation Assessment, Development and Evaluation (GRADE) methodology. A level of evidence was de ned for each bibliographic reference cited as a function of the type of study and could be reassessed in light of the meth- odological quality of the study. An overall level of evi- dence was determined for each endpoint, taking into account the level of evidence of each bibliographic ref- erence, the between-study consistency of the results, the direct or indirect nature of the results, and cost analysis. ree levels of proof were used (Table 1):

• A high overall level of evidence enabled formulation of a “strong” recommendation (should be done… GRADE 1+, should not be done… GRADE 1−).

• A moderate, low, or very low overall level of evidence led to the drawing up of an “optional” recommenda- tion (should probably be done… GRADE 2+, should probably not be done… GRADE 2−).

• When literature was inexistent or insu cient, the question could be the subject of a recommendation in the form of an expert opinion (the experts sug- gest…).

e proposed recommendations were presented and discussed one by one. e aim was not necessary to reach a single and convergent opinion of the experts on all the proposals, but to de ne the points of agreement and the points of disagreement or uncertainty. Each expert then reviewed and rated each recommendation using a scale of 1 (complete disagreement) to 9 (complete agreement). e collective rating was done using a GRADE grid. To approve a recommendation regarding a criterion, at least 50% of the experts had to be in agreement and less than 20% in disagreement. For an agreement to be strong, at least 70% of the experts had to be in agreement. In the absence of strong agreement, the recommendations were reformulated and rated again, with a view to reaching a consensus. Only expert opinions that elicited strong agreement were kept.

Areas of recommendations

ree areas were de ned: diagnostic strategy, referral of patients, and therapeutic management. A bibliographic search was conducted using the MEDLINE database via PubMed and the Cochrane database. For inclusion in the analysis, the publications had to be written in English or French. e analysis focused on all literature data without imposing a date limit, according to an order of appraisal ranging from meta-analyses to randomized trials to observational studies. e size of the study populations

Table 1 Recommendations according to the GRADE methodology

     

High level of evidence Moderate level of evidence Insu cient level of evidence Moderate level of evidence High level of evidence

Recommendation according to the GRADE methodology

Strong recommendation “… should be done…”

Optional recommendation
“… should probably be done…”

Recommendation in the form of an expert opinion “The experts suggest…”

Optional recommendation
“… should probably not be done…”

Strong recommendation “… should not be done…”

Grade 1+ Grade 2+ Expert opinion Grade 2− Grade 1−

 

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and the relevance of the research were considered for each study.

Summary of results

e summary of the results by the experts according to the GRADE method led to the drawing up of 29 guide- lines. Of these guidelines, 4 had a high level of evidence (GRADE 1±) and 10 a low level of evidence (GRADE 2±). e GRADE method was inapplicable to 15 guidelines, which resulted in expert opinions. After two rounds of scoring, a strong agreement was reached for all guidelines. Table 2 provides a summary of the recommendations.

First area: Diagnostic strategy

Should arterial blood gas measurements be performed
in the patients with a decreased plasma bicarbonate level when diagnosing acid–base imbalance?
R1.1— e experts suggest that arterial blood gas meas- urements be performed in patients with a decreased plasma bicarbonate level so as to eliminate respiratory alkalosis, con rm the diagnosis of metabolic acidosis, and test for mixed acidosis (EXPERT OPINION).

Rationale Acidosis is a pathophysiological process that may account for a decrease in blood pH that de nes acidemia. Two main mechanisms may be responsible: a decrease in plasma bicarbonate, de ning metabolic aci- dosis, and an increase in PaCO2, de ning respiratory aci- dosis. In the case of metabolic acidosis, the decrease in plasma bicarbonate either re ects the intervention of the bu er system related to an accumulation of non-respira- tory acids, or excessive loss of bicarbonate.

e pH can be kept normal through the decrease in PaCO2 obtained by compensating hyperventilation. Aci- demia occurs when respiratory compensation is insuf- cient. e PaCO2 value that maintains a normal pH, called the expected PaCO2, can be calculated using the formula: expected PaCO2 = 1.5 × [HCO3−] + 8 ± 2 mmHg [4, 5]. Blood gas measurements can be used to assess respiratory compensation and so detect mixed aci- demia: pH < 7.38, HCO3− < 20 mmol/L and measured PaCO2 > expected PaCO2.

As the decrease in plasma bicarbonate may also be related to a compensation mechanism of respira- tory alkalosis [6], blood gas measurements would allow elimination of respiratory alkalemia: pH>7.42 and PaCO2 < 38 mmHg.

Most studies that have measured the agreement and limits of agreement between venous and arterial blood gas measurements did not evaluate the clinical supe- riority of one method with respect to another for diag- nosis of metabolic acidosis and were conducted on moderate-sized groups of selected patients. A meta- analysis of studies comparing arterial and venous blood

gas measurements in patients in emergency rooms found excellent agreement between the arterial and venous pH (mean di erence −0.033 [95% CI −0.039 to 0.027]) [7]. A single study of the management of ketoacido- sis in the emergency room found that arterial blood gas measurements altered treatment in 3.7% of cases and changed disposition in 1% of cases [8]. ese modi ca- tions were deemed negligible and the authors concluded that the techniques were equivalent. Very good agree- ment between arterial and venous measurements of base de cit was also found in trauma patients [9, 10]. Similar results, with a mean pH di erence of 0.03 [95% CI − 0.02 to 0.08], were found in critically ill patients with meta- bolic acidosis of various causes, except ketoacidosis [11].

However, the agreement between venous and arterial blood gas measurements was much poorer for PaCO2. In a meta-analysis of studies comparing arterial and venous PaCO2 values in patients in the emergency room, the mean di erence was 4.41 mmHg [95% CI 2.55– 6.27], with limits of agreement ranging from −20.4 to 25.8 mmHg [7].

Is base de cit a better measurement than plasma bicarbonate in diagnosing metabolic acidosis? R1.2—Measurement of base de cit should probably not be preferred to that of plasma bicarbonate in identify- ing patients at risk of metabolic acidosis (GRADE 2−, STRONG AGREEMENT).

Rationale Clinical data are scarce and limited (obser- vational, retrospective studies) [12–14]. e two larg- est studies show that if the control group is of patients with a base excess (BE) of −5 mmol/L, corresponding to a base de cit of 5 mmol/L, plasma bicarbonate below 20 mmol/L is a good diagnostic indicator of metabolic acidosis [13, 14]. BE corresponds to the quantity of strong acid (or of strong base in the case of a metabolic acidosis) that should be added in vitro to 1 L of plasma to normalize the pH to 7.40, with a PaCO2 of 40 mmHg and a temperature of 37 °C. ere are several methods of calculating BE, but they all use plasma bicarbonate as the main component. Standard base excess (SBE) calculated using the van Slyke equation* takes into account a hemo- globin concentration of 5 g/dL which is the theoretical hemoglobin concentration in the extracellular space of bicarbonate distribution. e van Slyke equation for SBE is the most used clinically, but is not used in comparative studies with plasma bicarbonate. As BE is always calcu- lated from plasma bicarbonate, the correlation between plasma bicarbonate and BE (and hence base de cit) is very strong.

* Van Slyke equation: −

Base excess=(HCO3 –24.4)+(2.3×Hb+7.7)×(pH −7.4)×(1−0.023×Hb), with Hb in g/dL.

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Table 2 Summary of recommendations

Recommendation

Diagnostic strategy

. R1.1  The experts suggest that arterial blood gas measurements be performed in patients with a decreased plasma bicarbonate level so as to eliminate respiratory alkalosis, con rm the diagno‐
sis of metabolic acidosis, and test for mixed acidosis

. R1.2  Measurement of base de cit should probably not be preferred to that of plasma bicarbonate in identifying patients at risk of metabolic acidosis

. R1.3  The anion gap corrected for albumin should probably be used rather than the uncorrected anion gap to di erentiate acidosis related to acid load from acidosis related to base de cit

. R1.4  The experts suggest rst applying the Henderson–Hasselbalch method using the plasma anion gap corrected for albumin for the diagnosis of the mechanism of metabolic acidosis. However,
the Stewart method gives insight into situations unexplained by the Henderson–Hasselbalch method: acid–base imbalance secondary to blood sodium and chloride imbalance and com‐ plex disorders

. R1.5  The experts suggest using an algorithm to improve the etiological diagnosis of metabolic acidosis

. R1.6  The experts suggest that the urinary anion gap should only be calculated in metabolic acidosis without unmeasured anions or obvious etiology

. R1.7  The experts suggest that measurement of urinary pH should be restricted to patients with metabolic acidosis without unmeasured anions or obvious etiology, and with a strong clinical
suspicion of tubular acidosis

. R1.8  The experts suggest that a normal value of venous lactate discounts hyperlactatemia

. R1.9  Arterial lactate should probably be measured to con rm hyperlactatemia in case of increased venous lactate

. R1.10  Capillary blood lactate should not be measured to diagnose hyperlactatemia

. R1.11  Capillary blood ketones rather than urine ketones should be measured when diagnosing ketoacidosis

Patient assessment and referral

. R2.1  The pH value should probably not be used alone to identify critically ill patients

. R2.2  Hyperlactatemia, whatever its value, should be considered as a marker of severity in initial treat‐
ment. Diagnostic and therapeutic management should be rapid and multidisciplinary if needed

. R2.3  Increase in blood lactate should probably be controlled in the rst hours of management so as to assess the response to treatment

. R2.4  The experts suggest close monitoring of patients with diabetic ketoacidosis, ideally in an Intensive Care Unit

Therapeutic management

. R3.1  Insulin should probably be administered intravenously rather than subcutaneously in patients with diabetic ketoacidosis

. R3.2  An insulin bolus should probably not be administered before starting continuous intravenous insulin therapy in patients with diabetic ketoacidosis

. R3.3  Low continuous intravenous insulin doses should probably be administered in the treatment of diabetic ketoacidosis

. R3.4  The experts suggest using an initial dosage of 0.1 IU/kg/h without exceeding 10 IU/h, and to increase it in the absence of hypokalemia, if the targets for correction of blood ketones
(0.5 mmol/L/h), bicarbonate (3 mmol/L/h), and capillary blood glucose (3 mmol/L/h) are not reached after the rst hours of treatment

. R3.5  The experts suggest administering sodium bicarbonate to compensate for gastrointestinal or renal base loss in case of poor clinical tolerance

. R3.6  Sodium bicarbonate should probably be administered to intensive care patients with severe metabolic acidemia (pH ≤ 7.20, PaCO2 < 45 mmHg) and moderate to severe acute renal
insu ciency, so as to improve prognosis

. R3.7  Sodium bicarbonate should not be administered routinely in the therapeutic management of circulatory arrest, apart from pre‐existing hyperkalemia or poisoning by membrane stabilizers

. R3.8  Sodium bicarbonate should probably not be administered to patients with diabetic ketoacidosis

. R3.9  The experts suggest administering sodium bicarbonate in the therapeutic management of salicylate poisoning, whatever the pH value

Level of evidence

Expert opinion Grade 2−

Grade 2+ Expert opinion

Expert opinion Expert opinion Expert opinion

Expert opinion Grade 2+

Grade 1− Grade 1+

Grade 2− Grade 1+

Grade 2+ Expert opinion

Grade 2+ Grade 2− Grade 2+ Expert opinion

Expert opinion Grade 2+

Grade 1−

Grade 2− Expert opinion

      

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Table2 (continued)

R3.10 R3.11 R3.12 R3.13 R3.14

Recommendation

In case of shock and/or acute renal insu ciency, the experts suggest initiation of renal replace‐ ment therapy if the pH is below or equal to 7.15 in the absence of severe respiratory acidosis and despite appropriate treatment

In case of lactic acidosis suggestive of metformin poisoning, the experts suggest early initiation of renal replacement therapy when there is organ dysfunction or in the absence of improvement in the rst hours of therapeutic management

In case of methanol or ethylene glycol poisoning, the experts suggest initiation of renal replace‐ ment therapy if the anion gap is above 20 mEq/L or if there is renal insu ciency or visual impairment

In metabolic acidosis associated with salicylic acid poisoning, the experts suggest initiation of renal replacement therapy when there is neurological involvement and/or if the salicylic acid concentration is above 6.5 mmol/L (90 mg/dL) and/or if the pH is less than or equal to 7.20

The experts suggest compensating for acidemia by increasing respiratory frequency without inducing intrinsic positive end‐expiratory pressure, with a maximum of 35 cycles/min and/or
a tidal volume up to 8 mL/kg of body mass, and by monitoring plateau pressure. The aim of ventilation is not to normalize pH. A target pH greater than or equal to 7.15 seems reasonable. Medical treatment of metabolic acidosis and of its cause should be envisaged concomitantly, as ventilatory compensation can only be symptomatic and temporary

Level of evidence

Expert opinion Expert opinion Expert opinion Expert opinion Expert opinion

        

In case of metabolic acidosis, is the plasma anion gap corrected for albumin better than the uncorrected plasma anion gap in di erentiating acid excess from base de cit? R1.3— e anion gap corrected for albumin should probably be used rather than the uncorrected anion gap to di erentiate acidosis related to acid load from acidosis related to base de cit (GRADE 2+, STRONG AGREEMENT).

Rationale Although most clinical data are prospective, they are scarce and observational. Comparisons between the corrected anion gap* (cAG) and the uncorrected anion gap** (AG) show either no di erence [15, 16] or superiority of cAG [17–19]. Most authors consider that the pathological threshold is cAG or AG>12 mmol/L. e physiological AG is mainly composed of phosphate and albuminate (weak anion from blood albumin). Con- sequently, hypoalbuminemia leads to a decrease in plasma albuminate and so to a decrease in AG. Hence, a normal AG associated with hypoalbuminemia corre- sponds to the presence of plasma acids, which replace albuminate to normalize AG. Taking the albumin level into account in the calculation of AG unmasks plasma acids when there is hypoalbuminemia. So, cAG is greater than AG, particularly in a population of patients with a high risk of hypoalbuminemia, as is the case for patients in intensive care or patients with malnutrition, hepatopa- thy, chronic in ammation, or urinary loss of albumin.

* cAG=AG+(40−[albuminemia])×0.25, with albu- minemia in g/L.

** AG=Na+−(Cl−+HCO3−)=12±4 mmol/L (or AG =(Na++K+)−(Cl−+HCO3−)=16±4 mmol/L).

Is the Stewart method equivalent to the Henderson– Hasselbalch method using the anion gap corrected for albumin for the diagnosis of the mechanism
of metabolic acidosis?

R1.4— e experts suggest rst applying the Hender- son–Hasselbalch method using the anion gap corrected for albumin for the diagnosis of the mechanism of meta- bolic acidosis. However, the Stewart method provides insight into situations unexplained by the Henderson– Hasselbalch method: acid–base imbalance secondary to blood sodium and chloride imbalance and complex dis- orders (EXPERT OPINION).

Rationale e Henderson–Hasselbalch approach using the anion gap corrected for albumin and the Stewart method was proposed for the identi cation of causes of acid–base imbalances [17, 20–24]. e anion gap (AG) (or unmeasured anions) requires just a simple and rapid calculation*. At equilibrium, AG does not account for low-level cations that are not measured routinely (Mg2+, Ca2+, H+) and is essentially explained by anions not determined by blood electrolyte measurements (essen- tially albuminate and phosphate). An increase in AG classically indicates the accumulation of an acid whose anion is not chloride and theoretically corresponds to the accumulation of one of the following compounds: lactate, acetoacetate, hydroxybutyrate, oxalate, glyco- late, formate, salicylate, sulfate. However, this reasoning implies that the value of unmeasured anions, essentially albuminate, and more rarely phosphate (Pi), is nor- mal. Indeed, hypoalbuminemia results in a decrease in unmeasured anions and will reduce the anion gap [25].

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e accumulation of an anion like lactate or acetoacetate may therefore be missed, because AG is falsely normal. Albumin-correction AG (cAG)** identi es most situa- tions where there is accumulation of an anion other than chloride and hypoalbuminemia [26].

e Stewart approach assumes that the acid–base bal- ance is based on a dissociation of water molecules that depends on three independent variables: PaCO2, the strong ion di erence which corresponds to the di er- ence between strong cations and strong anions (appar- ent SID (appSID)=Na++K++Ca2++Mg2+−Cl−) and the sum of non-volatile weak acids present in dis- sociated or undissociated form (Atot) de ned by [albu- min×(0.123×pH−0.631)+[Pi×(0.309×pH−0.469]. Use is made of the e ective SID: e SID = HCO3− + albu- minate− + Pi− = HCO3− + Atot. Respiratory acid–base disturbances are exclusively de ned by increased PaCO2. e approach to metabolic acid–base disturbances requires calculation of the strong ion gap (SIG), which is equal to appSID—e SID. In the Stewart model, given that electrical neutrality must be respected, the varia- tion in bicarbonate concentration is the consequence of the acid–base disturbance and not its cause unlike the hypothesis of Henderson–Hasselbalch model. A positive SIG indicates the presence of unmeasured ani- ons and so of metabolic acidosis [27–29]. e Stewart approach appears at least equivalent to the Henderson– Hasselbalch approach in the case of accumulation of

endogenous or exogenous acid or loss of bicarbonate [17, 20, 22, 25]. However, the Stewart approach sheds light on metabolic disorders secondary to blood sodium and chloride levels, such as hyperchloremic acidosis associ- ated with saline uid resuscitation, which the Hender- son–Hasselbalch approach explains less easily [23, 26], and on complex disorders (hyperlactatemia at normal pH and BE) [30–32].

* AG=Na+−(Cl−+HCO3−)=12±4 mmol/L (or AG =(Na++K+)−(Cl−+HCO3−)=16±4 mmol/L).

** cAG=AG+(40−[blood albumin])×0.25, with blood albumin in g/L.

Does the use of a diagnostic algorithm improve etiological diagnosis of metabolic acidosis?
R1.5— e experts suggest using an algorithm to improve the etiological diagnosis of metabolic acidosis (EXPERT OPINION) (Fig. 1).

Rationale Few studies have evaluated the diagnostic impact of the use of an algorithm in metabolic acidosis, so it is di cult to provide a well-argued answer to the question. It is always essential to collect data by clinical history taking and physical examination [33]. Apart from the exceptions mentioned below, the use of an algorithm could subsequently be used to investigate simple set- tings of acidosis [28]. However, it is important to know if there are artifacts [34] or atypical [35], complex [33], or misleading clinical pictures [30, 36]. Acetylsalicylic

 

Fig. 1 Algorithm recommended by the experts for etiological diagnosis of metabolic acidemia (EXPERT OPINION)

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acid poisoning associates initial respiratory alkalosis with metabolic acidosis responsible for an increase in the anion gap which is only partly explained by the accumu- lation of acetylsalicylic acid [33]. e increased anion gap acidosis seen in ethylene glycol poisoning is in part due to the accumulation of glycolic acid, which some laboratory analyzers misidentify as lactate [34, 37]. Diabetic ketoaci- dosis may be accompanied by hyperchloremic acidosis at hospital admission or a few hours after admission [35]. e association of lactate production with vomiting may lead to the clinical picture of metabolic alkalosis [30]. Abundant infusion of chloride-rich uid during circula- tory insu ciency associated with hyperlactatemia pro- duces hyperchloremic acidosis [30, 38]. It is important to remember that the respiratory compensation observed in acute metabolic acidosis cannot correct the pH value beyond 7.40 (Fig. 1). Main causes of hyperlactatemia are listed in Table 3.

If no etiology is found, a hereditary metabolic disorder may be considered.

Should the urinary anion gap always be calculated
in metabolic acidosis?
R1.6— e experts suggest that the urinary anion gap should only be calculated in metabolic acidosis with- out unmeasured anions or obvious etiology (EXPERT OPINION).

Rationale e urinary anion gap, calculated as the

sum of measured anions and cations (Na++K++Cl−),

was proposed for estimation of the urinary excretion of

+

e diagnostic utility of the urinary anion gap, notably in the emergency room or in intensive care is, however, questionable. First, outside intensive care, the perfor- mance of this index is only validated by studies of very low level of evidence [6, 40, 41]. e urinary anion gap seems to be correlated with NH4+ excretion [28], but the correlation is weak, the reported variability is substantial, and none of the available studies adjust for confounding factors or report the diagnostic performance [6, 40, 41]. Second, the discriminating character and the contribu- tion to diagnosis are not evaluated. Lastly, most studies conducted in the emergency room or in intensive care have not evaluated this parameter [22, 23, 27].

A single study suggests a high prevalence of tubular aci- dosis in intensive care. It is of low level of evidence, as the parameter used (urinary anion gap) is also a diagnostic

Table3 Main causes of hyperlactatemia suggested by the experts (EXPERT OPINION)

Type A
Severe anemia
Septic, hemorrhagic, cardiogenic shock CO poisoning
Organ ischemia
Convulsions
Intense physical exercise

Type B
Sub‐type B1—Underlying primary diseases

Cancer and hemopathy Decompensated diabetes HIV infection
Liver failure

Sepsis
Severe malaria attack

Sub‐type B2—Medication and toxins Alcohol
Beta‐adrenergic agents
Cyanide and cyanogenic compounds Diethyl ether

Fluorouracil (5‐FU)
Halothane
Iron
Isoniazid
Linezolid
Metformin
Nalidixic acid
Niacin (vitamin B3 or nicotinic acid) Nucleoside reverse transcriptase inhibitors Paracetamol

Propofol
Psychostimulants: cocaine, amphetamines, cathinones Salicylates
Strychnine
Sugars: fructose, sorbitol, xylitol
Sulfasalazine
Total parenteral nutrition
Valproic acid
Vitamin de ciency: thiamine (vitamin B1) and biotin (vitamin B8)

Sub‐type B3—Inborn errors of metabolism Fructose‐1,6‐diphosphatase de ciency Glucose‐6‐phosphatase de ciency (von Gierke disease) Kearns–Sayre syndrome

MELAS syndrome
MERRF syndrome
Methylmalonic acidemia (methylmalonyl‐CoA mutase de ciency) Pearson syndrome
Pyruvate carboxylase de ciency
Pyruvate dehydrogenase de ciency

criterion of the expected clinical picture (tubular acido- sis) [42].

Should urinary pH always be measured in metabolic acidosis?
R1.7— e experts suggest that measurement of urinary pH should be restricted to patients with metabolic aci- dosis without unmeasured anions or obvious etiology, and with a strong clinical suspicion of tubular acidosis (EXPERT OPINION).

ammonium (NH4 ) [39–41]. In acidosis with a normal anion gap, ammonium distinguishes between acidosis related to gastrointestinal loss of bicarbonate (negative urinary anion gap), acidosis linked to tubular acidosis, or hyporeninemic hypoaldosteronism (zero or increased anion gap) [39–41].

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Rationale e measurement of urinary pH is less well validated than calculation of the urinary anion gap. Its diagnostic value is controversial and seems more restricted [28, 36, 39, 41].

Is measurement of venous lactate less e ective
than measurement of arterial lactate in diagnosing hyperlactatemia?
R1.8— e experts suggest that a normal value of venous lactate discounts hyperlactatemia (EXPERT OPINION).

R1.9—Arterial lactate should probably be measured to con rm hyperlactatemia in case of increased venous lac- tate (GRADE 2+, STRONG AGREEMENT).

Rationale Measurement of arterial lactate is the ref- erence method for determining blood lactate. Venous blood is more easily sampled than arterial blood and less painful for the patient. Several studies have evalu- ated the agreement between measurements of venous and arterial blood lactate. A 2014 meta-analysis included three of these studies [7]. ey were prospective or ret- rospective cohort studies involving patient selection bias (non-consecutive patients), blood lactate was rarely above 4 mmol/L, and the measurement equipment and sampling conditions di ered from one study to another. e mean bias in the results ranged from −0.016 to 1.06 mmol/L. e Bland–Altman limits of agreement ranged from −1.51 to 2.65 mmol/L. ese biases and limits, reported for the usual lactate values, show that measurement of venous lactate is inadequate for the diagnosis of hyperlactatemia.

Measurement of venous lactate has also been assessed in prognostic cohort studies of patients with severe trauma, suspected septic shock, or admitted to the emer- gency room [43–46]. e study populations were not all comparable and the results were not unequivocal, in particular for venous lactate values below 4 mmol/L. On the other hand, it seems that a venous lactate value above 4 mmol/L was strongly associated with an increased risk of death.

In conclusion, whereas the measurement of venous lactate can be useful in determining the prognosis, the literature data do not support its use in the diagnosis of hyperlactatemia.

Is the measurement of capillary blood lactate as e ective
as measurement of arterial lactate in diagnosing hyperlactatemia?
R1.10—Capillary blood lactate should not be measured to diagnose hyperlactatemia (GRADE 1−, STRONG AGREEMENT).

Rationale e measurement of capillary blood lactate is less invasive and faster than measurement of arterial

lactate. Several cohort studies have compared these two methods of measurement. Mean bias ranged from − 0.99 to 2.4 mmol/L. e Bland–Altman limits of agree- ment ranged from −5.6 to 5.4 mmol/L [47–51]. ese results are di cult to analyze because di erent meas- uring equipment was used and there are inconsisten- cies between the results [52]. Measurement of capillary blood lactate is therefore insu ciently e cient and does not allow su ciently accurate determination of arterial lactate.

Measurement of capillary blood lactate has been pro- posed as a prognostic tool. Most studies, conducted before hospital admission or upon admission to the emergency room, have combined several sampling tech- niques (venous and capillary). Few studies have analyzed measurement of capillary blood lactate as a prognostic tool for patients with severe trauma or suspected septic shock [44, 47, 53]. ese studies were of low level of evi- dence and do not allow a conclusion to be drawn regard- ing the prognostic value of measurement of capillary blood lactate.

Hyperlactatemia occurs when there is an imbalance between lactate production and clearance [54]. Tradi- tionally, the causes of hyperlactatemia have been divided into two groups: associated with tissue hypoxia (type A) and without tissue hypoxia (type B) [55, 56]. However, the mechanism can be mixed and the same etiology can be found in both groups [57].

Is measurement of capillary blood ketones more e ective than measurement of urine ketones in diagnosing ketoacidosis?
R1.11—Capillary blood ketones rather than urine ketones should be measured when diagnosing ketoacido- sis (GRADE 1+, STRONG AGREEMENT).

Rationale Studies comparing urine ketones and blood ketones are all observational. ere is just one rand- omized controlled prospective study, but it evaluated the incidence of hospitalization/emergency assessment among patients with type 1 diabetes depending on self- measurement of blood ketones or urine ketones [58]. Most studies have included patients presenting to the emergency room because of a hyperglycemic episode (blood glucose generally > 2.5 g/L). e diagnostic criteria of diabetic ketoacidosis varied from one study to another, which makes comparison di cult. Whatever their qual- ity, all the studies found greater speci city and a quicker diagnostic result with capillary blood ketones, for a com- parable sensitivity. In addition, urine ketones may persist in the absence of signi cant blood ketones. Lastly, meas- urement of urine ketones determines only acetoacetate, whereas measurement of blood ketones determines solely

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beta-hydroxybutyrate, which is the predominant ketone body in the case of diabetic ketosis. Depending on the various cut-o s reported, blood ketones above 3 mmol/L associated with hyperglycemia constitute a good diag- nostic criterion of diabetic ketoacidosis [59–63].

Second area: Patient assessment and referral

In case of metabolic acidosis, is the pH value useful to identify critically ill patients?
R2.1— e pH value should probably not be used alone to identify critically ill patients (GRADE 2−, STRONG AGREEMENT).

Rationale e blood pH is a fundamental laboratory parameter. Its value depends not only on metabolic or res- piratory variations, but also on the site of arterial, venous, or capillary blood sampling. Clinical studies of the prog- nostic utility of blood pH in emergency medicine have used analysis of venous or arterial blood. e emergence of new tools for point-of-care measurement of pH has yielded recent published studies of its prognostic value before hospital admission. ese observational studies essentially related to non-traumatic cardiac arrest and most failed to show a prognostic utility of the isolated measure- ment of pH [64, 65]. However, there is a need to assess pH combined with other clinical and biochemical parameters. Most in-hospital studies were observational, were limited by small numbers of patients, and assessed very di er- ent diseases (cardiac arrest, trauma, pneumonia, diabetic ketoacidosis). Most of them failed to show any prognostic value of pH measurement [8, 66, 67]. Only those studies of acute community-acquired pneumonia underscored the utility of the measurement of blood pH, but in the context of severity scores combined with other parameters [68, 69].

Is lactate measurement useful to identify critically ill patients?
R2.2—Hyperlactatemia, whatever its value, should be considered as a marker of severity in initial treatment. Diagnostic and therapeutic management should be rapid and multidisciplinary if needed (GRADE 1+, STRONG AGREEMENT).

R2.3—Increase in blood lactate should probably be monitored in the rst hours of management so as to assess the response to treatment (GRADE 2+, STRONG AGREEMENT).

Rationale Numerous studies show an association between initial blood lactate and the prognosis of septic shock and trauma. ey are mostly retrospective cohort studies or prospective observational studies. eir meth- odologies are often questionable and their levels of proof limited. Nonetheless, all the studies agree on the util- ity of early measurement of arterial or venous lactate

in evaluating the severity of septic shock and the need for critical care [70]. Hyperlactatemia is an independ- ent index of severity and an initial lactate level above 4 mmol/L in septic shock [71] and above 2 mmol/L in trauma patients [72–74] is always associated with a worse prognosis [71, 75].

Several studies report the additional prognostic use- fulness of plasma lactate decrease (clearance). e best cut-o seems to be 30% lactate clearance at the sixth hour of treatment in septic shock [76]. Likewise, no lac- tate decrease or a decrease of less than 20% in the rst 2- to 4-h is associated with a worse prognosis in trauma patients [77].

Initial hyperlactatemia is also associated with a greater treatment burden. Pre-admission measurement of lactate improves identi cation of patients needing intensive care [43].

Does intensive monitoring of patients with diabetic ketoacidosis improve prognosis?
R2.4— e experts suggest close monitoring of patients with diabetic ketoacidosis, ideally in intensive care unit (EXPERT OPINION).

Rationale e indication for admission to intensive care is clear in the case of organ failure associated with ketoacidosis. However, for several decades certain studies have suggested that patients with uncomplicated diabetic ketoacidosis can be managed by conventional hospi- tal care [78–80]. One retrospective cohort study in over 15,000 patients in 159 American hospitals showed that the use of intensive care for diabetic ketoacidosis patients was not associated with di erences in mortality or length of hospital stay [81]. However, the results are di cult to interpret and generalize as it was a retrospective study based on coding data in which no clinical or paraclini- cal nding concerning the severity of ketoacidosis was provided. Moreover, the criteria of admission to inten- sive care were not indicated. As continuous intravenous insulin therapy is generally necessary and potentially serious complications can appear during therapeutic management (hypokalemia, hypoglycemia, pulmonary edema, cerebral edema), close clinical and paraclinical monitoring is indispensable. Since this monitoring may be compromised in conventional hospital care because of organizational di culties, patients with diabetic ketoaci- dosis should be admitted to intensive care so as to adapt the treatment and watch for potential side e ects.

Third area: Therapeutic management

During diabetic ketoacidosis, what route of insulin delivery should be preferred?
R3.1—Insulin should probably be administered intra- venously rather than subcutaneously in patients

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with diabetic ketoacidosis (GRADE 2+, STRONG AGREEMENT).

Rationale Two literature reviews have considered the optimal route for administration of insulin in diabetic ketoacidosis [82, 83]. Four controlled and randomized trials compared subcutaneous (SC) insulin with intrave- nous (IV) insulin in management of diabetic ketoacido- sis in adults [84–87]. All evaluated the rate of correction of acidosis or the normalization of blood glucose. ree evaluated the length of hospital stay [85–87]. A lack of precision in the reported results meant that one of these studies [84] could not be included in the meta-analysis of the rate of correction of acidosis or normalization of blood glucose. is trial described a correction of ketosis and a signi cantly greater decrease in blood glucose at 2 h in the IV group, but non-signi cant results 4, 6, and 8 h after the start of therapeutic management. A meta-analy- sis of two trials comparing similar insulins [85, 87] found no signi cant di erence in the rate of correction of acido- sis or the normalization of blood glucose (di erence = 0.2 h; 95% con dence interval [−1.7–2.1]; p=0.81). e last trial [86] reported similar results (d=−1 h [−3.2–1.2]; p=0.36). e meta-analyses found no signi cant di er- ence in the e ect of the route of administration on the length of hospital stay. e literature data do not show that IV insulin therapy is preferable to SC insulin therapy, in terms of the rate of correction of acidosis, the nor- malization of blood glucose, or the length of hospital stay. However, few patients were included and they presented uncomplicated ketoacidosis. In addition, SC injections of insulin were performed regularly and the frequency of injections could be a source of discomfort or even pain.

As a venous route was often necessary, the continuous IV route seems preferable so as to facilitate restoration of water–electrolyte balance, avoid repeated SC injections, and reduce the risk of hypoglycemia, while ensuring bet- ter control of the insulin dose administered.

During diabetic ketoacidosis, should an insulin bolus be administered before starting continuous intravenous insulin therapy?
R3.2—An insulin bolus should probably not be adminis- tered before starting continuous intravenous insulin ther- apy in patients with diabetic ketoacidosis (GRADE 2−, STRONG AGREEMENT).

Rationale A literature review of the use of an initial insulin bolus before initiation of continuous intrave- nous insulin therapy identi ed just one randomized controlled trial [88] and one observational study [89]. In the latter, the normalization of blood glucose and the length of hospital stay did not di er signi cantly between the bolus and non-bolus groups (change in blood glu- cose 60.1±38.2 vs 56.0±45.4 mg/dL/h, respectively;

p = 0.54; length of hospital stay 5.6 ± 5.3 vs 5.9 ± 6.9 days; p=0.81). e authors noted more cases of hypoglycemia in the bolus group, but the di erence was not statistically signi cant (6 vs 1%; p = 0.12). e randomized controlled trial compared three groups: a low-dose insulin bolus then a low insulin dose (0.07 IU/kg, then 0.07 IU/kg/h), a low insulin dose without an initial bolus (0.07 IU/kg/h), and double-dose insulin (0.14 IU/kg/h) without an initial bolus. e rate of correction of acidosis, the normaliza- tion of blood glucose, and the length of hospital stay did not di er between the three groups. It is important to note that this study did not evaluate the insulin dose commonly used in continuous intravenous administra- tion, i.e., 0.1 IU/kg/h.

During diabetic ketoacidosis, should high or low continuous intravenous insulin doses be administered?
R3.3—Low continuous intravenous insulin doses should probably be administered in the treatment of diabetic ketoacidosis (GRADE 2+, STRONG AGREEMENT).

R3.4— e experts suggest using an initial dosage of 0.1 IU/kg/h without exceeding 10 IU/h, and to increase it in the absence of hypokalemia, if the targets for cor- rection of blood ketones (0.5 mmol/L/h), bicarbonate (3 mmol/L/h), and capillary blood glucose (3 mmol/ L/h) are not reached after the rst hours of treatment (EXPERT OPINION).

Rationale e literature data, essentially from the 1970s, indicate that low continuous intravenous insulin doses are as e ective as higher doses [90, 91]. A literature review found two trials (with no control group) report- ing a decrease in blood glucose that was similar for low and high insulin doses. e risk of hypokalemia, hypogly- cemia, or cerebral edema possibly associated with high doses and e cacy of low doses have justi ed their use in practice for several decades. However, if the targets for correction of blood ketones (0.5 mmol/L/h) or fail- ing that of bicarbonate (3 mmol/L/h) and blood glucose (3 mmol/L/h) are not reached, it is possible to envisage increased doses, provided there is no hypokalemia.

Should sodium bicarbonate infusion be used in severe metabolic acidosis and, if so, in what situations?
R3.5— e experts suggest administering sodium bicar- bonate to compensate for gastrointestinal or renal base loss in case of poor clinical tolerance (EXPERT OPINION).

Rationale e administration of sodium bicarbonate could limit the deleterious cardiovascular, respiratory, and cellular energy e ects of loss of bicarbonate [2]. Sodium bicarbonate should be administered carefully as it is asso- ciated with a risk of hypokalemia, hypernatremia, hypocal- cemia, rebound alkalemia, and water–sodium overload [2].

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R3.6—Sodium bicarbonate should probably be admin- istered to intensive care patients with severe metabolic acidemia (pH≤7.20, PaCO2<45 mmHg) and moder- ate to severe acute renal insu ciency (GRADE 2+, STRONG AGREEMENT).

Rationale Metabolic acidosis accompanying states of shock is often multifactorial, with hyperlactatemia and renal insu ciency being involved rst and foremost, plus potentially associated loss of bicarbonate. Several retro- spective, observational, single-center [92–94] or prospec- tive, multicenter studies [95] were insu cient to draw conclusions regarding the role of sodium bicarbonate. Two randomized, prospective, crossover, single-center physiological studies in 10 [96] and 14 patients [97] con- cluded that administration of sodium bicarbonate did not have a more favorable e ect than saline solution on hemodynamic parameters measured by pulmonary arte- rial catheter in patients with metabolic lactic acidosis (blood bicarbonate≤22 or 17 mmol/L and arterial blood lactate > 2.5 mmol/L).

A controlled, randomized, prospective multicenter study in 400 patients (pH ≤ 7.20, blood bicarbo- nate ≤ 20 mmol/L and PaCO2 ≤ 45 mmHg and blood lac- tate > 2 mmol/L or SOFA score > 4) compared the e ect of sodium bicarbonate administration (4.2% q.s. pH≥7.30) with the absence of such administration on a principal composite endpoint (day-28 mortality and/or presence of at least one organ failure at day 7, according to the SOFA score). e authors reported no e ect of alkalinization (71% of patients in the control arm and 66% of patients in the bicarbonate arm reached the composite endpoint; the estimated absolute di erence was −5.5% ([95% CI − 15.2% to 4.2%], p = 0.24). e probability of day 28 sur- vival was 46% [95% CI − 40% to 54%] in the control group and 55% [95% CI 49% to 63%]; p = 0.09 in the bicarbonate group.

In the a priori de ned stratum “acute renal insu – ciency—AKIN 2–3,” 74 (82%) of the 90 patients of the control group and 64 (70%) of the 92 patients of the bicar- bonate group reached the composite endpoint (estimated absolute di erence: −12.3%, 95% CI −26.0% to −0.1%; p = 0.0462). e probability of survival at day 28 was 46% [95% CI 35% to 55%] in the control group and 63% [95% CI 52% to 72%] in the bicarbonate group (p = 0.0283).

ese results were con rmed in multivariate analysis. In the general population and the “acute renal insu – ciency” stratum, the patients randomized to the control arm received renal replacement therapy (RRT) more often and for longer than the patients of the bicarbonate arm (52% need for RRT in the control arm vs 35% in the bicarbonate arm, p < 0.001) [98].

R3.7—Sodium bicarbonate should not be administered routinely in the therapeutic management of circulatory

arrest, apart from pre-existing hyperkalemia or poison- ing by membrane stabilizers (GRADE 1−, STRONG AGREEMENT).

Rationale Since the 1999 French consensus confer- ence, the role of sodium bicarbonate alkalinization in the therapeutic management of the cardiac arrest has been evaluated in 5 retrospective studies [99–103] and a pro- spective, randomized, double-blind, controlled multi- center study [104]. Four retrospective studies showed an increase in the frequency of resumption of spontaneous circulatory activity in patients treated with sodium bicar- bonate [99, 101–103] and one reported decreased hospi- tal survival in patients treated with sodium bicarbonate [100]. e randomized clinical trial (792 patients) found no di erence in survival between the patients treated with sodium bicarbonate (7.4%) and those receiving a placebo (6.7%, p = 0.88). e use of sodium bicarbonate in patients could be reserved for pre-existing hyper- kalemia or poisoning by membrane stabilizers [105].

R3.8—Sodium bicarbonate should probably not be administered to patients with diabetic ketoacidosis (GRADE 2−, STRONG AGREEMENT).

Rationale e administration of sodium bicarbonate transiently increases pH and may limit the deleterious cardiovascular and cellular energy e ects of acidemia. However, the administration of sodium bicarbonate is associated with a risk of hypokalemia, hypernatremia, hypocalcemia, rebound alkalemia, and water–sodium overload [2]. A pathophysiological study in 39 patients has recently shown altered microvascular endothelial reactivity at the acute phase of diabetic ketoacidosis. is endothelial dysfunction was more marked when the arterial pH was below 7.20 and the vascular reactivity improved after 24 h of treatment. However, the admin- istration of sodium bicarbonate was not tested in this observational study [106].

Since the 1999 French consensus conference, the role of sodium bicarbonate alkalinization in therapeutic man- agement of ketoacidosis was reassessed in a retrospective single-center study [107] comparing 44 patients treated with bicarbonate and 42 untreated patients. e authors found no e ect of sodium bicarbonate on the rate of cor- rection of acidemia, as in previous studies, all of which were conducted in small populations [108].

R3.9— e experts suggest administering sodium bicar- bonate in the therapeutic management of salicylate poi- soning, whatever the pH value (EXPERT OPINION).

Rationale Salicylate poisoning is rare and potentially fatal. Toxicological expertise is needed to ensure optimal therapeutic management. e aim of bicarbonate admin- istration is twofold: induce alkalemia to limit the passage of salicylate into the central nervous system and alkalini- zation of urine to promote renal excretion of salicylate

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[109, 110]. An old observational study in a small number of patients suggested that simple alkalinization leads to renal excretion of salicylate equal to or even greater than that of forced diuresis, alkaline diuresis, or not [111]. e administration of sodium bicarbonate should be sub- ject to close monitoring as it is associated with a risk of hypokalemia, hypernatremia, hypocalcemia, alveolar hypoventilation, and uid overload [2, 109]. In the case of severe poisoning, the experts suggest renal replacement therapy (cf. R3.13) and continued alkalinization between renal replacement therapy sessions until salicylate is completely eliminated.

Should renal replacement therapy be used in severe metabolic acidosis, and if so in what situations?
R3.10 In case of shock and/or acute renal insu ciency, the experts suggest initiation of renal replacement ther- apy if the pH is below or equal to 7.15 in the absence of severe respiratory acidosis and despite appropriate treat- ment (EXPERT OPINION).

Rationale ere are no randomized controlled studies with mortality as the main endpoint that compare the initiation or not of renal replacement therapy in severe metabolic acidosis. e recommendations presented here come mostly from retrospective observational stud- ies and case reports.

According to a questionnaire administered by the European Society of Intensive Care Medicine, 74% of intensivists consider metabolic acidosis (without indica- tion of severity) to be a criterion for initiation of renal replacement therapy [112].

e plasma bicarbonate or pH cut-o authorizing renal replacement therapy could be deduced from the results of randomized studies comparing the e ect on mortality of early or delayed initiation of renal replacement therapy in acute renal insu ciency. In 101 surgery patients, Wald et al. [113] found no di erence in mortality as a function of the timing of renal replacement therapy, and plasma bicarbonate at its initiation was similar in the two groups: 20.7±4.3 vs 20.1±4.4 mmol/L. In 231 surgery patients with KDIGO stage-2 acute renal insu ciency, Zarbock et al. [114] found at initiation of renal replacement ther- apy similar plasma bicarbonate levels in the early and late arms: 20.9±3.6 mmol/L vs 20.7±3.7 mmol/L. Mortality was signi cantly lower in the early initiation group.

In the AKIKI study [115] in 619 patients with KDIGO stage-3 acute renal insu ciency, intention-to-treat analy- sis showed that pH and plasma bicarbonate were signi – cantly lower in the late renal replacement therapy group (hard criteria for renal replacement therapy, including pH ≤ 7.15, rate of renal replacement therapy: 50%) than in the early renal replacement therapy group (6 h after inclusion, rate of renal replacement therapy: 100%):

bicarbonate 16.6±5.6 vs 18.9±4.9 mmol/L (p<0.001) and pH 7.25 ± 0.15 vs 7.30 ± 0.12 (p < 0.001). ere was no di erence in mortality between groups.

e IDEAL ICU study [116] included 488 septic shock patients with RIFLE stage F acute renal insu ciency ran- domized to 2 arms (renal replacement therapy started within 12 h following inclusion, rate of renal replacement therapy 97% versus renal replacement therapy started 48 h after inclusion in the absence of resolution of acute renal insu ciency, rate of renal replacement therapy: 62%). ere was no di erence in mortality (58 vs 54%) and the study was stopped as medical care was deemed futile. A pH≤7.15 was a criterion for initiation of renal replacement therapy. Of the 41 patients in the late arm, 20 had a pH of 7.10.

e BICAR-ICU study [98] compared intrave- nous administration of 4.2% sodium bicarbonate (q.s. pH > 7.30) with a control arm without infusion of bicarbo- nate in patients with severe metabolic acidosis (pH ≤ 7.20, bicarbonate < 20 mmol/L and PaCO2 ≤ 45 mmHg) and a SOFA score ≥ 4 or arterial blood lactate ≥ 2 mmol/L. is randomized, controlled, intention-to-treat study was strati ed according to age, AKIN stage 2 or 3 acute renal insu ciency,andsepticshock.Renalreplacementtherapy was used if 2 of the 3 following criteria applied: pH < 7.20 after 24 h, hyperkalemia, or urine output < 0.3 mL/kg/h over 24 h. In the acute renal insu ciency sub-group of 182 patients, the probability of survival at day 28 was 46% [95% CI 35% to 55%] in the control group and 63% [95% CI 52% to 72%] in the bicarbonate group (p = 0.0283).

R3.11—In case of lactic acidosis suggestive of met- formin poisoning, the experts suggest early initiation of renal replacement therapy when there is an organ dys- function or in the absence of improvement in the rst hours of therapeutic management (EXPERT OPINION).

Rationale Metformin-associated lactic acidosis is de ned by arterial lactate above 5 mmol/L and pH below 7.35 during metformin treatment. Its incidence is low: from 10 to 12/100,000 [117, 118]. A 2015 literature review identi ed 175 publications (no randomized trial) reporting high mortality (30 to 50%) [119].

Yeh H-C et al. [117] collated case reports and studies from 1977 to 2014 (3 studies, 142 case reports) in 253 patients and found a mortality of 16.2%. Factors associ- ated with mortality were mechanical ventilation and lac- tate level (17 vs 22 mmol/L, p < 0.01), but not pH, plasma bicarbonate, or level of metformin. A lactate level above 20 mmol/L was signi cantly associated with mortality.

A retrospective study conducted in Northern Italy from 2010 to 2015 collated 117 cases and reported 78.3% survival [118]. On average, at initiation of renal replace- ment therapy, the pH was below 7.04 and blood lactate above 12 mmol/L.

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As the metformin dose is not always available and its prognostic value is subject to discussion [119], renal replacement therapy should be initiated without delay when there is an organ dysfunction or when there is no improvement in the rst hours of therapeutic manage- ment. Renal replacement therapy is intended to correct water–electrolyte and acid–base disturbances and to ensure metformin clearance [119].

R3.12—In case of methanol or ethylene glycol poison- ing, the experts suggest initiation of renal replacement therapy if the anion gap is above 20 mEq/L or if there is renal insu ciency or visual impairment (EXPERT OPINION).

Rationale Methanol poisoning and ethylene glycol poi- soning are rare and potentially fatal. Expertise is needed to ensure optimal therapeutic management including, if necessary, speci c intensive care procedures.

In alcohol poisoning (methanol and ethylene glycol), the pH at admission is correlated with the prognosis [120, 121]. A pH below 7.0 is predictive of death [122], whereas a pH above 7.22 is associated with survival [123]. e plasma anion gap (>24 mEq/L or>20 mEq/L in the case of hemodynamic instability) is correlated with the level of formate and with the prognosis [124].

Circulating methanol is removed by the kidney with a clearance of about 5 to 6 mL/min, which represents approximately 25 to 50% of its systemic elimination before its conversion to formic acid (responsible for the toxicity). is conversion is inhibited by intravenous administration of ethanol or fomepizole. e clear- ance of methanol achieved by intermittent hemodialysis ranges between 77 and 400 mL/min, and between 17 and 48 mL/min if renal replacement therapy is continuous [125, 126].

R3.13—In metabolic acidosis associated with salicylic acid poisoning, the experts suggest initiation of renal replacement therapy when there is neurological involve- ment and/or if the salicylic acid concentration is above 6.5 mmol/L (90 mg/dL) and/or if the pH is less than or equal to 7.20 (EXPERT OPINION).

Rationale Salicylate poisoning is rare and potentially fatal. Expertise is needed to ensure optimal therapeutic management comprising, if necessary, speci c intensive care procedures.

A 2015 literature review by a group of experts [110] found 84 publications, 80 of which related to case reports or patient cohorts and to a randomized controlled trial, and collated 143 patients with salicylate poisoning. e authors concluded that salicylic acid is highly dialyz- able and that intermittent hemodialysis is the preferred modality. ey also concluded that development of aci- demia should be considered as a warning sign because it indicates the onset of an organ dysfunction (lactic

acidosis, ketoacidosis, renal, and/or respiratory insu – ciency). In addition, the presence of acidemia increases the entry of salicylate into the central nervous system and the risk of cerebral edema.

A more recent retrospective study [127] in 56 mechani- cally ventilated patients with blood salicylate above 50 mg/dL reported 76% mortality. Failure to use renal replacement therapy was associated with increased mor- tality and survival was zero when blood salicylate was above 5.8 mmol/L, i.e., 80 mg/dL. However, no data were available on potential poisoning with other compounds or on the causes of death.

Given the limited volume and quality of the data, it is di cult to determine a toxic threshold accurately. How- ever, it appears that above 6.5 mmol/L (90 mg/dL) the risk of death is high, even in the absence of clinical signs.

Should minute ventilation be increased in mechanically ventilated patients with metabolic acidosis?
R3.14— e experts suggest compensating for acidemia by increasing respiratory frequency without inducing intrinsic positive end-expiratory pressure, with a maxi- mum of 35 cycles/min and/or a tidal volume up to 8 mL/ kg of body mass, and by monitoring plateau pressure. e aim of ventilation is not to normalize pH. A target pH greater than or equal to 7.15 seems reasonable. Medical treatment of metabolic acidosis and of its cause should be envisaged concomitantly, as ventilatory compensa- tion can only be symptomatic and temporary (EXPERT OPINION).

Rationale e control of breathing brings into play three types of interconnected structures: the control center commonly called the “respiratory centers” in the central nervous system at the level of the brainstem; the motor components of the respiratory system comprising the muscles of the upper airways, the thoracic cage, and the abdomen; and the receptors (chemoreceptors, muscle proprioceptors, airway and lung receptors) that transmit setpoints constantly to the respiratory centers (PCO2, pH, lung distension, respiratory muscle load…). us, the respiratory centers receive sensory and humoral infor- mation that enables homeostasis, while optimizing the energy cost of each respiratory cycle. e central chem- oreceptors on the ventral side of the brainstem respond rapidly and strongly to minimal variations in the pH and PCO2 of the cerebrospinal uid and blood. e hydrogen ion seems to be a determinant stimulus [128].

In metabolic acidosis, the physiological response is an increase in alveolar ventilation [129] that is constant, whatever the cause and severity of acidosis [130]. e stimulation of chemoreceptors in metabolic acidosis is responsible for an increase in tidal volume rather than tachypnea [130, 131]. Its e cacy depends not only on

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alveolar ventilation, but also on the hemodynamic state and integrity of the respiratory system [129, 132].

As yet there are no speci c data concerning venti- latory management of intubated-ventilated patients with metabolic acidosis. ough acidosis is conven- tionally associated with a poor prognosis [133], it has potentially protective e ects. Apart from the severity of acidosis, its mechanism and how it arises seem to be prognostic factors that should be taken into account.

e correction of metabolic acidosis by increasing respiratory frequency and/or tidal volume is question- able. Current data on protective ventilation are abun- dant and recommend keeping a tidal volume of about 6 mL/kg of body mass. Given the hemodynamic e ects of metabolic acidosis, it seems reasonable to adapt the respiratory frequency to achieve a pH greater than or equal to 7.15 [134–136], without exceeding 35 cycles/ min, as data in animal models suggest that a high min- ute ventilation has deleterious e ects [137, 138], which are more marked when there is lung involvement.

Abbreviations

BE: base excess; SBE: standard base excess; AG: anion gap; cAG: corrected anion gap; SID: strong ion di erence; e SID: e ective strong ion di erence; app SID: apparent strong ion di erence; IV: intravenous; SC: subcutaneous; RRT : renal replacement therapy.

Acknowledgements

Not applicable.

Authors’ contributions

BJ and MM proposed the elaboration of this recommendation and manuscript in agreement with the “Société de Réanimation de Langue Française” and “Société Française de Médecine d’Urgence”; NB and PGC wrote the methodol‐ ogy section and gave the nal version with the nal presentation. DV, AL, EM, MD, MM, and JL contributed to elaborate recommendations and wrote the rationale of « Diagnostic strategy ». YEC, JL , and MO contributed to elaborate recommendations and to write the rationale of « Patient assessment and referral ». YY, BJ, KK , and NT contributed to elaborate recommendations and

to write the rationale of « Therapeutic management ». All authors provided references. BJ, MM, PGC, and NB drafted the manuscript. All authors read and approved the nal manuscript.

Funding

This work was nancially supported by the Société de Réanimation de Langue Française (SRLF) and the Société Française de Médecine d’Urgence (SFMU).

Ethics approval and consent to participate

Not applicable.

Consent for publication

Not applicable.

Competing interests

The authors declare the following competing interests: B. Jung: Sedana Medical, Medtronic; M. Martinez: Astra Zeneca, Actélion; YE Claessens: Roche diagnostics, BioMérieux, Sano , P zer; M. Darmon: Sano , Gilead‐Kite, Astute Medical, MSD, Astellas; A. Lautrette: Baxter, Frésénius; J. Levraut: LFB, Nova‐ Biomedical; E. Maury: General Electric Healthcare, Doran International, Vygon, AstraZeneca; N. Terzi: Boehringer Ingelheim, P zer; D. Viglino: Astra Zeneca, Mundipharma; Y. Yordanov: Mundipharma, Sano ; PG Claret: Aspen, AstraZen‐ eca, Daiichi Sankyo, Roche Diagnostics, Sano , Thermo Fisher Scienti c. The remaining authors declare that they have no competing interests.

Author details

1 Département de Médecine Intensive et Réanimation, CHU Montpellier, 34000 Montpellier, France. 2 INSERM U‐1046, CNRS U‐9234 (PhyMedExp), Université de Montpellier, Montpellier, France. 3 Pôle Urgence, CH du Forez, 42605 Montbrison, France. 4 Réseau d’urgence Ligérien Ardèche Nord (REULIAN), Centre Hospitalier Le Corbusier, 42700 Firminy, France. 5 Départe‐ ment de Médecine d’urgence, Centre Hospitalier Princesse‐Grace, Avenue Pasteur, 98012 Monaco, France. 6 Unité de Médecine Intensive et Réanima‐ tion, Hôpital Universitaire Saint‐Louis, Assistance Publique–Hôpitaux de Paris, Avenue Claude‐Vellefaux, 75010 Paris, France. 7 Faculté de Médecine, Univer‐ sité Paris‐Diderot, Sorbonne–Paris‐Cité, Paris, France. 8 France Inserm, ECSTRA Team, UMR 1153, Centre d’Epidémiologie et de Biostatistique, CRESS, Biostatis‐ tics and Clinical Epidemiology, Sorbonne–Paris‐Cité, Paris, France. 9 Départe‐ ment de Médecine Intensive–Réanimation, CHU Lapeyronie, 371, Avenue Doyen‐Gaston‐Giraud, 34295 Montpellier, France. 10 Réanimation, Centre Jean‐ Perrin, CHU de Clermont‐Ferrand, 63000 Clermont‐Ferrand, France. 11 LMGE, UMR CNRS 6023, Université Clermont‐Auvergne, Clermont‐Ferrand, France.

12 Département de Médecine d’urgence, CHU de Nice, Hôpital Pasteur‐II,
30, Avenue de la Voie Romaine, 06000 Nice, France. 13 UFR de Médecine, Université de Nice Côte d’Azur, Avenue de Vallombrose, 06000 Nice, France.
14 Service de Médecine Intensive–Réanimation, Hôpital Saint‐Antoine, Assis‐ tance Publique–Hôpitaux de Paris, 184, Rue du Faubourg‐Saint‐Antoine, 75571 Paris Cedex 12 Paris, France. 15 Sorbonne Université, Université Pierre‐et‐Marie Curie‐Paris‐VI, Paris, France. 16 Inserm U1136, 75012 Paris, France. 17 Structure des Urgences, Centre Hospitalier de Cahors, 335, Rue Wilson, 46000 Cahors, France. 18 Service de Médecine Intensive–Réanimation, Centre Hospitalier Universitaire de Grenoble, Université de Grenoble, Grenoble, France. 19 Inserm, U1042, Université Grenoble‐Alpes, HP2, 38000 Grenoble, France. 20 Service

des Urgences Adultes, CS 10217, CHU Grenoble‐Alpes, 38043 Grenoble Cedex 09 Grenoble, France. 21 Inserm U1042, Laboratoire HP2 Hypoxie‐Physiopathol‐ ogies, Université Grenoble‐Alpes, Grenoble, France. 22 Faculté de Médecine, Sorbonne Universités, 75013 Paris, France. 23 Inserm, U1153, Université Paris‐ Descartes, 75006 Paris, France. 24 Service des Urgences, Hôpital Saint‐Antoine, Assistance Publique–Hôpitaux de Paris (AP–HP), 75012 Paris, France. 25 Pôle Anesthésie Réanimation Douleur Urgences, Centre Hospitalier Universitaire de Nîmes, 4, Rue du Professeur‐Robert‐Debré, 30029 Nîmes, France.

Received: 26 June 2019

References

Accepted: 30 July 2019

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