Crit Care Med 2009;37:2733-2739

To describe the composition of metabolic acidosis in patients with severe sepsis and septic shock at intensive care unit admission and throughout the first 5 days of intensive care unit stay. Design: Prospective, observational study.

Setting
Twelve-bed intensive care unit.

Patients
Sixty patients with either severe sepsis or septic shock.

Interventions
None.

Measurements and main results
Data were collected until 5 days after intensive care unit admission. We studied the contribution of inorganic ion difference, lactate, albumin, phosphate, and strong ion gap to metabolic acidosis. At admission, standard base excess was -6.69 +/- 4.19 mEq/L in survivors vs. -11.63 +/- 4.87 mEq/L in nonsurvivors (p < .05); inorganic ion difference (mainly resulting from hyperchloremia) was responsible for a decrease in standard base excess by 5.64 +/- 4.96 mEq/L in survivors vs. 8.94 +/- 7.06 mEq/L in nonsurvivors (p < .05); strong ion gap was responsible for a decrease in standard base excess by 4.07 +/- 3.57 mEq/L in survivors vs. 4.92 +/- 5.55 mEq/L in nonsurvivors with a nonsignificant probability value; and lactate was responsible for a decrease in standard base excess to 1.34 +/- 2.07 mEq/L in survivors vs. 1.61 +/- 2.25 mEq/L in nonsurvivors with a nonsignificant probability value. Albumin had an important alkalinizing effect in both groups; phosphate had a minimal acid-base effect. Acidosis in survivors was corrected during the study period as a result of a decrease in lactate and strong ion gap levels, whereas nonsurvivors did not correct their metabolic acidosis. In addition to Acute Physiology and Chronic Health Evaluation II score and serum creatinine level, inorganic ion difference acidosis magnitude at intensive care unit admission was independently associated with a worse outcome.

Conclusions
Patients with severe sepsis and septic shock exhibit a complex metabolic acidosis at intensive care unit admission, caused predominantly by hyperchloremic acidosis, which was more pronounced in nonsurvivors. Acidosis resolution in survivors was attributable to a decrease in strong ion gap and lactate levels.

Crit Care Med 2009;37:2827-2839

To decide whether the use of blood lactate monitoring in critical care practice is appropriate. We performed a systematic health technology assessment as blood lactate monitoring has been implemented widely but its clinical value in critically ill patients has never been evaluated properly.

Data source
PubMed, other databases, and citation review.

Study selection
We searched for lactate combined with critically ill patients as the target patient population. Two reviewers independently selected studies based on relevance for the following questions: Does lactate measurement: 1) perform well in a laboratory setting? 2) provide information in a number of clinical situations? 3) relate to metabolic acidosis? 4) increase workers’ confidence? 5) alter therapeutic decisions? 6) result in benefit to patients? 7) result in similar benefits in your own setting? result in benefits which are worth the extra costs?

Data extraction and synthesis
We concluded that blood lactate measurement in critically ill patients: 1) is accurate in terms of measurement technique but adequate understanding of the (an)aerobic etiology is required for its correct interpretation; 2) provides not only diagnostic but also important prognostic information; 3) should be measured directly instead of estimated from other acid-base variables; 4) has an unknown effect on healthcare workers’ confidence; 5) can alter therapeutic decisions; 6) could potentially improve patient outcome when combined with a treatment algorithm to optimize oxygen delivery, but this has only been shown indirectly; 7) is likely to have similar benefits in critical care settings worldwide; and has an unknown cost-effectiveness.

Conclusions
The use of blood lactate monitoring has a place in risk-stratification in critically ill patients, but it is unknown whether the routine use of lactate as a resuscitation end point improves outcome. This warrants randomized controlled studies on the efficacy of lactate-directed therapy

NHS National Library of Health

From October 2006 the Association of Surgeons of Great Britain and Ireland, SARS, BAPEN Medical, the Intensive Care Society, the Association for Clinical Biochemistry and the Renal Association nominated core members of a steering committee who came together to establish consensus for good perioperative fluid prescribing. Concern arose from a high incidence of postoperative sodium and water overload, and evidence to suggest that preventing or treating this, by more accurate fluid therapy, would improve outcome.

Intensive Care Med 2008:34;2226-2234

To determine whether there was a difference between epinephrine and norepinephrine in achieving a mean arterial pressure (MAP) goal in intensive care (ICU) patients.

Design
Prospective, double-blind, randomised-controlled trial.

Setting
Four Australian university-affiliated multidisciplinary ICUs.

Patients and participants
Patients who required vasopressors for any cause at randomisation. Patients with septic shock and acute circulatory failure were analysed separately.

Interventions
Blinded infusions of epinephrine or norepinephrine to achieve a MAP =70 mmHg for the duration of ICU admission.

Measurements
Primary outcome was achievement of MAP goal >24 h without vasopressors. Secondary outcomes were 28 and 90-day mortality. Two hundred and eighty patients were randomised to receive either epinephrine or norepinephrine. Median time to achieve the MAP goal was 35.1 h (interquartile range (IQR) 13.8ñ70.4 h) with epinephrine compared to 40.0 h (IQR 14.5ñ120 h) with norepinephrine (relative risk (RR) 0.88; 95% confidence interval (CI) 0.69ñ1.12; P = 0.26). There was no difference in the time to achieve MAP goals in the subgroups of patients with severe sepsis (n = 158; RR 0.81; 95% CI 0.59ñ1.12; P = 0.18) or those with acute circulatory failure (n = 192; RR 0.89; 95% CI 0.62ñ1.27; P = 0.49) between epinephrine and norepinephrine. Epinephrine was associated with the development of significant but transient metabolic effects that prompted the withdrawal of 18/139 (12.9%) patients from the study by attending clinicians. There was no difference in 28 and 90-day mortality.

Conclusions
Despite the development of potential drug-related effects with epinephrine, there was no difference in the achievement of a MAP goal between epinephrine and norepinephrine in a heterogenous population of ICU patients.

Critical Care 2008,12:R14

Metformin-associated lactic acidosis (MALA) is a classical side effect of metformin and is known to be a severe disease with a high mortality rate. MALA’s treatment by dialysis is controversial and is subject to many case reports. We aimed to assess the prevalence of MALA in a 16-bed, university-affiliated, intensive care unit (ICU), and the effect of dialysis on patients’ outcome.

Methods
Over a 5-year period, we retrospectively identified all patients who either were admitted into the ICU with metformin as a usual medication, or who attempted suicide by metformin ingestion. Within this population, we selected patients presenting with a lactic acidosis, thus defining MALA, and described their clinical and biological features.

Results
Metformin-associated lactic acidosis accounted for 0.84% of all admissions during the studied period (30 MALA admissions over 5 years) and was associated with a 30% mortality rate. The only factors associated with a fatal outcome were the reason for admission in the ICU and the initial prothrombin time. Although patients who went on to hemodialysis had higher illness severity scores, as compared to those who were not dialyzed, the mortality rates were similar between the two groups (31.3% versus 28.6%).

Conclusions
Metformin-associated lactic acidosis can be encountered in the ICU several times a year and still remains a life-threatening condition. Treatment is mostly restricted to supportive measures, although hemodialysis may possess a protective effect.

Anaesthesia 2008;63:1043-1045

It is estimated by the International Diabetes Federation that 246 million adults worldwide have diabetes mellitus and the figure is expected to reach 380 million by 2025. Anaesthetists will be involved in the care of more diabetic patients as they present in increasing numbers for surgery as a result of the complications of diabetes. The cornerstone of metabolic control in the peri-operative period, except for Type II diabetics undergoing minor surgery, is the administration of intravenous (iv) glucose with potassium chloride and a variable insulin infusion. Standard anaesthetic and surgical texts recommend the use of 5% or 10% glucose at a rate of 125–83 ml^.h⁻¹. This corresponds to practice in nine out of 11 acute hospitals in the East Anglia region as shown by the authors’ recent audit (unpublished results). It is likely, therefore, that this regimen is common nationally.

Br. J. Anaesth. 2008;101:141-150

The advent of balanced solutions for i.v. fluid resuscitation and replacement is imminent and will affect any specialty involved in fluid management. Part of the background to their introduction has focused on the non-physiological nature of ‘normal’ saline solution and the developing science about the potential problems of hyperchloraemic acidosis. This review assesses the physiological significance of hyperchloraemic acidosis and of acidosis in general. It aims to differentiate the effects of the causes of acidosis from the physiological consequences of acidosis. It is intended to provide an assessment of the importance of hyperchloraemic acidosis and thereby the likely benefits of balanced solutions.

Clin Sci 2003;104:17-24

In this double-blind crossover study, the effects of bolus infusions of 0.9% saline (NaCl) and Hartmann’s solution on serum albumin, haematocrit and serum and urinary biochemistry were compared in healthy subjects. Nine young adult male volunteers received 2-litre intravenous infusions of 0.9% saline and Hartmann’s solution on separate occasions, in random order, each over 1h. Body weight, haematocrit and serum biochemistry were measured pre-infusion and at 1h intervals for 6h. Biochemical analysis was performed on pooled post-infusion urine. Blood and plasma volume expansion, estimated by dilutional effects on haematocrit and serum albumin, were greater and more sustained after saline than after Hartmann’s solution (P<0.01). At 6h, body weight measurements suggested that 56% of the infused saline was retained, in contrast with only 30% of the Hartmann’s solution. Subjects voided more urine (median: 1000 compared with 450ml) of higher sodium content (median: 122 compared with 73mmol) after Hartmann’s than after saline (both P = 0.049), despite the greater sodium content of the latter. The time to first micturition was less after Hartmann’s than after saline (median: 70 compared with 185min; P = 0.008). There were no significant differences between the effects of the two solutions on serum sodium, potassium, urea or osmolality. After saline, all subjects developed hyperchloraemia (>105mmol/l), which was sustained for >6h, while serum chloride concentrations remained normal after Hartmann’s (P<0.001 for difference between infusions). Serum bicarbonate concentration was significantly lower after saline than after Hartmann’s (P = 0.008). Thus excretion of both water and sodium is slower after a 2-litre intravenous bolus of 0.9% saline than after Hartmann’s solution, due possibly to the more physiological [Na+]/[Cl-] ratio in Hartmann’s solution (1.18:1) than in saline (1:1) and to the hyperchloraemia caused by saline.

Critical Care 2007, 11:R130

Metabolic acidosis during hemorrhagic shock is common and conventionally considered to be due to hyperlactatemia. There is increasing awareness, however, that other nonlactate, unmeasured anions contribute to this type of acidosis.

Methods
Eleven anesthetized dogs were hemorrhaged to a mean arterial pressure of 45 mm Hg and were kept at this level until a metabolic oxygen debt of 120 mLO2/kg body weight had evolved. Blood pH, partial pressure of carbon dioxide, and concentrations of sodium, potassium, magnesium, calcium, chloride, lactate, albumin, and phosphate were measured at baseline, in shock, and during 3 hours post-therapy. Strong ion difference and the amount of weak plasma acid were calculated. To detect the presence of unmeasured anions, anion gap and strong ion gap were determined. Capillary electrophoresis was used to identify potential contributors to unmeasured anions.

Results
During induction of shock, pH decreased significantly from 7.41 to 7.19. The transient increase in lactate concentration from 1.5 to 5.5 mEq/L during shock was not sufficient to explain the transient increases in anion gap (+11.0 mEq/L) and strong ion gap (+7.1 mEq/L), suggesting that substantial amounts of unmeasured anions must have been generated. Capillary electrophoresis revealed increases in serum concentration of acetate (2.2 mEq/L), citrate (2.2 mEq/L), α-ketoglutarate (35.3 μEq/L), fumarate (6.2 μEq/L), sulfate (0.1 mEq/L), and urate (55.9 μEq/L) after shock induction.

Conclusion
Large amounts of unmeasured anions were generated after hemorrhage in this highly standardized model of hemorrhagic shock. Capillary electrophoresis suggested that the hitherto unmeasured anions citrate and acetate, but not sulfate, contributed significantly to the changes in strong ion gap associated with induction of shock.

BJA 2004;92:54-60

The Fencl-Stewart approach to acid-base disorders uses five equations of varying complexity to estimate the base excess effects of the important components: the strong ion difference (sodium and chloride), the total weak acid concentration (albumin) and unmeasured ions. Although this approach is straightforward, most people would need a calculator to use the equations. We proposed four simpler equations that require only mental arithmetic and tested the hypothesis that these simpler equations would have good agreement with more complex Fencl-Stewart equations.

Methods
We reduced two complex equations for the sodium±chloride effect on base excess to one simple equation: sodium±chloride effect (meq litre-1)=[Na+]-[Cl-]-38. We simplified the equation of the albumin effect on base excess to an equation with two constants: albumin effect (meq litre-1)=0.25x(42-[albumin]g litre-1). Using 300 blood samples from critically ill patients, we examined the agreement between the more complex Fencl-Stewart equations and our simplified versions with Bland-Altman analyses.

Results
The estimates of the sodium-chloride effect on base excess agreed well, with no bias and limits of agreement of -0.5 to 0.5 meq litre-1. The albumin effect estimates required log transformation. The simpliÆed estimate was, on average, 90% of the Fencl±Stewart estimate. The limits of agreement for this percentage were 82-98%.

Conclusions
The simplified equations agree well with the previous, more complex equations.Our findings suggest a useful, simple way to use the Fencl-Stewart approach to analyse acid-base disorders in clinical practice.

Critical Care Medicine 2007;35:2390-2394

Metabolic acidosis is common in septic shock, yet few data exist on its etiological temporal profile during resuscitation; this is partly due to limitations in bedside monitoring tools (base excess, anion gap). Accurate identification of the type of acidosis is vital, as many therapies used in resuscitation can themselves produce metabolic acidosis.

Design
Retrospective, cohort study.

Setting
Multidisciplinary pediatric intensive care unit with 20 beds.

Patients
A total of 81 children with meningococcal septic shock.

Interventions
None.

Measurements and Results
Acid-base data were collected retrospectively on 81 children with meningococcal septic shock (mortality, 7.4%) for the 48 hrs after presentation to the hospital. Base excess was partitioned using abridged Stewart equations, thereby quantifying the three predominant influences on acid-base balance: sodium chloride, albumin, and unmeasured anions (including lactate). Metabolic acidosis was common at presentation (mean base excess, -9.7 mmol/L) and persisted for 48 hrs. However, the pathophysiology changed dramatically from one of unmeasured anions at admission (mean unmeasured anion base excess, -9.2 mmol/L) to predominant hyperchloremia by 8-12 hrs (mean sodium-chloride base excess, -10.0 mmol/L). Development of hyperchloremic acidosis was associated with the amount of chloride received during intravenous fluid resuscitation (r2 = .44), with the base excess changing, on average, by -0.4 mmol/L for each millimole per kilogram of chloride administered. Hyperchloremic acidosis resolved faster in patients who 1) manifested larger (more negative) sodium chloride-partitioned base excess, 2) maintained a greater urine output, and 3) received furosemide; and slower in those with high blood concentrations of unmeasured anions (all, p < .05).

Conclusions
Hyperchloremic acidosis is common and substantial after resuscitation for meningococcal septic shock. Recognition of this entity may prevent unnecessary and potentially harmful prolonged resuscitation.

Critical Care Medicine 2007;35:2456-2457

Fluid resuscitation is a vital part of critical care. We use massive amounts of fluids in our daily critical care practice. Almost all of these fluids contain strong ions (such as sodium and chloride) and, sometimes, weak acids (such as albumin). Thus, it is easy to imagine that massive fluid resuscitation can result in metabolic changes that alter a patient’s acid-base status. Saline-induced metabolic acidosis has been well described; it has been explained by so-called dilution of the bicarbonate concentration. Recently, however, the Stewart methodology has been applied to critical care medicine; it has revealed that this acidosis is primarily due to a decreased strong ion difference (SID) induced by hyperchloremia.

According to Stewart’s concept, neither bicarbonate nor hydrogen ion is an independent determinant of the acid-base status, whereas strong ion difference and total weak acid (ATOT) are independent variables. Thus, the balance between strong ions and weak acids, including albumin, phosphate, and unmeasured anions, plays an important role in acid-base physiology. Using this methodology, studies have shown that metabolic acid-base disorders have a complex etiology, which could not be previously understood using bicarbonate-oriented methodology.

Critical Care Medicine 2007;35:2390-2394

Metabolic acidosis is common in septic shock, yet few data exist on its etiological temporal profile during resuscitation; this is partly due to limitations in bedside monitoring tools (base excess, anion gap). Accurate identification of the type of acidosis is vital, as many therapies used in resuscitation can themselves produce metabolic acidosis.

Design
Retrospective, cohort study.

Setting
Multidisciplinary pediatric intensive care unit with 20 beds.

Patients
A total of 81 children with meningococcal septic shock.

Interventions
None.

Measurements and Results
Acid-base data were collected retrospectively on 81 children with meningococcal septic shock (mortality, 7.4%) for the 48 hrs after presentation to the hospital. Base excess was partitioned using abridged Stewart equations, thereby quantifying the three predominant influences on acid-base balance: sodium chloride, albumin, and unmeasured anions (including lactate). Metabolic acidosis was common at presentation (mean base excess, -9.7 mmol/L) and persisted for 48 hrs. However, the pathophysiology changed dramatically from one of unmeasured anions at admission (mean unmeasured anion base excess, -9.2 mmol/L) to predominant hyperchloremia by 8-12 hrs (mean sodium-chloride base excess, -10.0 mmol/L). Development of hyperchloremic acidosis was associated with the amount of chloride received during intravenous fluid resuscitation (r2 = .44), with the base excess changing, on average, by -0.4 mmol/L for each millimole per kilogram of chloride administered. Hyperchloremic acidosis resolved faster in patients who 1) manifested larger (more negative) sodium chloride-partitioned base excess, 2) maintained a greater urine output, and 3) received furosemide; and slower in those with high blood concentrations of unmeasured anions (all, p < .05).

Conclusions
Hyperchloremic acidosis is common and substantial after resuscitation for meningococcal septic shock. Recognition of this entity may prevent unnecessary and potentially harmful prolonged resuscitation.

Intensive Car Med 1997; 23:282-287

Objectives
To compare the effects of norepinephrine and dobutamine to epinephrine on hemodynamics, lactate metabolism, and gastric tonometric variables in hyperdynamic dopamine-resistant septic shock.

Design
A prospective, intervention, randomized clinical trial.
Setting
Adult medical/surgical intensive care unit in a university hospital.

Patients
30 patients with a cardiac index (CI) > 3.5 l · min^-1 · m^-2 and a mean arterial pressure (MAP) h 60 mmHg after volume loading and dopamine 20 ug/kg/min and either oliguria or hyperlactatemia.

Interventions
Patients were randomized to receive an infusion of either norepinephrine-dobutamine or epinephrine titrated to obtain an MAP greater than 80 mmHg with a stable or increased CI.

Measurements and main results
Baseline measurements included: hemodynamic and tonometric parameters, arterial and mixed venous gases, and lactate and pyruvate blood levels. These measurements were repeated after 1, 6, 12, and 24 h. All the patients fulfilled the therapeutic goals. No statistical difference was found between epinephrine and norepinephrine-dobutamine for systemic hemodynamic measurements. Considering metabolic and tonometric measurements and compared to baseline values, after 6 h, epinephrine infusion was associated with an increase in lactate levels (from 3.1 - 1.5 to 5.9 - 1.0 mmol/l; p < 0.01), while lactate levels decreased in the norepinephrine-dobutamine group (from 3.1 - 1.5 to 2.7 - 1.0 mmol/l). The lactate/pyruvate ratio increased in the epinephrine group (from 15.5 - 5.4 to 21 - 5.8; p < 0.01) and did not change in the norepinephrine-dobutamine group (13.8 - 5 to 14 - 5.0). Gastric mucosal pH (pHi) decreased (from 7.29 - 0.11 to 7.16 - 0.07; p < 0.01) and the partial pressure of carbon dioxide (PCO₂) gap (tonometer PCO₂ – arterial PCO₂) increased (from 10 - 2.7 to 14 - 2.7 mmHg; p < 0.01) in the epinephrine group. In the norepinephrine-dobutamine group pHi (from 7.30 - 0.11 to 7.35 - 0.07) and the PCO₂ gap (from 10 - 3.0 to 4 - 2.0 mmHg) were normalized within 6 h (p < 0.01). The decrease in pHi and the increase in the lactate/pyruvate ratio in the epinephrine group was transient, since it returned to normal within 24 h.

Conclusions
Considering the global hemodynamic effects, epinephrine is as effective as norepinephrine-dobutamine. Nevertheless, gastric mucosal acidosis and global metabolic changes observed in epinephrine-treated patients are consistent with a markedly inadequate, although transient, splanchnic oxygen utilization. The metabolic and splanchnic effects of the combination of norepinephrine and dobutamine in hyperdynamic dopamine-resistant septic shock appeared to be more predictable and more appropriate to the current goals of septic shock therapy than those of epinephrine alone.