Tag Archives: metabolic


Hyperchloraemia and mortality

Here’s something to add to the pile of data cautioning us to think before we acidify patients with saline. A study in Anesthesia and Analgesia using propensity matching provides retrospective evidence that patients who developed hyperchloremia after noncardiac surgery had worse outcomes.

For more information on why saline isn’t ‘normal’ see: What’s with all the chloride? An assault on salt

Hyperchloremia after noncardiac surgery is independently associated with increased morbidity and mortality: a propensity-matched cohort study
Anesth Analg. 2013 Aug;117(2):412-21


BACKGROUND: The use of normal saline is associated with hyperchloremic metabolic acidosis. In this study, we sought to determine the incidence of acute postoperative hyperchloremia (serum chloride >110 mEq/L) and whether this electrolyte disturbance is associated with an increase in length of hospital stay, morbidity, or 30-day postoperative mortality.

METHODS: Data were retrospectively collected on consecutive adult patients (>18 years of age) who underwent inpatient, noncardiac, nontransplant surgery between January 1, 2003 and December 31, 2008. The impact of postoperative hyperchloremia on patient morbidity and length of hospital stay was examined using propensity-matched and logistic multivariable analysis.

RESULTS: The dataset consisted of 22,851 surgical patients with normal preoperative serum chloride concentration and renal function. Acute postoperative hyperchloremia (serum chloride >110 mmol/L) is quite common, with an incidence of 22%. Patients were propensity-matched based on their likelihood to develop acute postoperative hyperchloremia. Of the 4955 patients with hyperchloremia after surgery, 4266 (85%) patients were matched to patients who had normal serum chloride levels after surgery. These 2 groups were well balanced with respect to all variables collected. The hyperchloremic group was at increased risk of mortality at 30 days postoperatively (3.0% vs 1.9%; odds ratio = 1.58; 95% confidence interval, 1.25-1.98) (relative risk 1.6 or risk increase of 1.1%) and had a longer hospital stay (7.0 days [interquartile range 4.1-12.3] compared with 6.3 [interquartile range 4.0-11.3]) than patients with normal postoperative serum chloride levels. Patients with postoperative hyperchloremia were more likely to have postoperative renal dysfunction. Using all preoperative variables and measured outcome variables in a logistic regression analysis, hyperchloremia remained an independent predictor of 30-day mortality with an odds ratio of 2.05 (95% confidence interval, 1.62-2.59).

CONCLUSION: This retrospective cohort trial demonstrates an association between hyperchloremia and poor postoperative outcome. Additional studies are required to demonstrate a causal relationship between these variables.

Point of care analysis of intraosseous samples

Some good news for remote, rural, prehospital, and retrieval medicine clinicians who rely on point of care testing with the i-STAT® device. An animal study confirmed the reliability of testing aspirates from intraosseous samples taken from the tibia(1).

This is also good news for hospital practitioners when it comes to the acquisition of blood gas results, since there are concerns over the potential damage to blood gas analysers by bone marrow contents in the samples.

The researchers tested blood gases, acid–base status, lactate, haemoglobin, and electrolytes, and compared these with results from an arterial sample.

There was no malfunction of the equipment. Most of the acid–base parameters showed discrepancies between arterial and osseous samples: the average pH and base excess were consistently lower whilst pCO2 and lactate were higher in the intraosseous samples compared to the arterial. However the overall small degree and predictable direction of discrepancy in these values should preserve the clinical usefulness of intraosseous gases if these findings can be replicated in human subjects. pO2 was obviously very different between osseous and arterial samples.

They noted that aspiration of intraosseous samples was generally straightforward, especially immediately after placement of the cannulae, but on a few occasions more forceful aspiration was needed. They point out that this could possibly cause cellular lysis and affect the potassium analysis.

The authors consider the issue of how much aspirate should be discarded before taking a sample after intraosseous cannula insertion, and refer to a prior study which suggested that 2mL is adequate.

Summary
  • Intraosseous aspirate can be tested on an i-STAT® point-of-care analyser
  • Haemoglobin and electrolytes show good correlation with arterial samples
  • Acid-base, pCO2, and lactate differ slightly from arterial results but in a predictable direction and results are still likely to be clinically useful in an emergency
  • It may be worth discarding the first 2 ml of aspirate
  • These results require validation in human subjects

Analysis of intraosseous samples using point of care technology–an experimental study in the anaesthetised pig
Resuscitation. 2012 Nov;83(11):1381-5


BACKGROUND: Intraosseous access is an essential method in emergency medicine when other forms of vascular access are unavailable and there is an urgent need for fluid or drug therapy. A number of publications have discussed the suitability of using intraosseous access for laboratory testing. We aimed to further evaluate this issue and to study the accuracy and precision of intraosseous measurements.

METHODS: Five healthy, anaesthetised pigs were instrumented with bilateral tibial intraosseous cannulae and an arterial catheter. Samples were collected hourly for 6h and analysed for blood gases, acid base status, haemoglobin and electrolytes using an I-Stat point of care analyser.

RESULTS: There was no clinically relevant difference between results from left and right intraosseous sites. The variability of the intraosseous sample values, measured as the coefficient of variance (CV), was maximally 11%, and smaller than for the arterial sample values for all variables except SO2. For most variables, there seems to be some degree of systematic difference between intraosseous and arterial results. However, the direction of this difference seems to be predictable.

CONCLUSION: Based on our findings in this animal model, cartridge based point of care instruments appear suitable for the analysis of intraosseous samples. The agreement between intraosseous and arterial analysis seems to be good enough for the method to be clinically useful. The precision, quantified in terms of CV, is at least as good for intraosseous as for arterial analysis. There is no clinically important difference between samples from left and right tibia, indicating a good reproducibility.

Hyperglycaemia & mortality in sepsis – lactate dependent?

I like this paper for introducing a new concept to me. For years the critical care community has recognised the link between hyperglycaemia and mortality, leading to early recommendations of intensive insulin regimens subsequently shown not to be of benefit. Now it appears that the association between hyperglycaemia and mortality may be less relevant in patients with a normal lactate.

In a study of adult nondiabetic critically ill patients, hyperglycaemia had a significant association with increased mortality risk using simple univariate analysis. When they adjusted for concurrent hyperlactataemia however, hyperglycaemia was not significantly associated with increased mortality risk.

The authors discuss several known or postulated aspects of interplay between lactate and glucose in sepsis:

  • Hyperlactataemia appears to inhibit glucose uptake by muscle cells and decrease activity of the GLUT-4 transporters
  • Hyperlactataemia has also been shown to increase insulin resistance directly
  • Glucose and lactate levels tend to be elevated simultaneously in severe sepsis at baseline.
  • Experimentally it has been estimated that 45% of infused (radiolabelled) lactate is either converted into glucose via gluconeogenesis or is transformed into glycogen via the Cori cycle, representing a higher proportion of glucose formation from lactate than in nonseptic controls.
  • It is possible that elevated glucose and lactate levels in sepsis both may be measures of the same phenomenon: glucose accumulates due to the sympathomimetic response to a systemic infection with increased catecholamine levels leading to increased activity of the Na+K+-ATPase, resulting in accumulation of adenosine diphosphate (ADP). Increased levels of ADP in turn augment glycogenolysis.
  • Mitochondrial metabolism cannot meet the increased cellular energy needs of sepsis, resulting in accumulation of ADP and leading to cytosolic glycolysis and lactate production, even in an aerobic environment.

The augmented glycolysis of sepsis (and during adrenergic therapy such as epinephrine/adrenaline or albuterol/salbutamol) is one of the causes of a raised lactate to consider when applying the LACTATES mnemonic I like to use.

Hyperlactatemia affects the association of hyperglycemia with mortality in nondiabetic adults with sepsis
Acad Emerg Med. 2012 Nov;19(11):1268-75


BACKGROUND: Admission hyperglycemia has been reported as a mortality risk factor for septic nondiabetic patients; however, hyperglycemia’s known association with hyperlactatemia was not addressed in these analyses.

OBJECTIVES: The objective was to determine whether the association of hyperglycemia with mortality remains significant when adjusted for concurrent hyperlactatemia.

METHODS: This was a post hoc, nested analysis of a retrospective cohort study performed at a single center. Providers had identified study subjects during their emergency department (ED) encounters; all data were collected from the electronic medical record (EMR). Nondiabetic adult ED patients hospitalized for suspected infection, two or more systemic inflammatory response syndrome (SIRS) criteria, and simultaneous lactate and glucose testing in the ED were enrolled. The setting was the ED of an urban teaching hospital from 2007 to 2009. To evaluate the association of hyperglycemia (glucose > 200 mg/dL) with hyperlactatemia (lactate ≥ 4.0 mmol/L), a logistic regression model was created. The outcome was a diagnosis of hyperlactatemia, and the primary variable of interest was hyperglycemia. A second model was created to determine if coexisting hyperlactatemia affects hyperglycemia’s association with mortality; the main outcome was 28-day mortality, and the primary risk variable was hyperglycemia with an interaction term for simultaneous hyperlactatemia. Both models were adjusted for demographics; comorbidities; presenting infectious source; and objective evidence of renal, respiratory, hematologic, or cardiovascular dysfunction.

RESULTS: A total of 1,236 ED patients were included, and the median age was 77 years (interquartile range [IQR] = 60 to 87 years). A total of 115 (9.3%) subjects were hyperglycemic, 162 (13%) were hyperlactatemic, and 214 (17%) died within 28 days of their initial ED visits. After adjustment, hyperglycemia was significantly associated with simultaneous hyperlactatemia (odds ratio [OR] = 4.14, 95% confidence interval [CI] = 2.65 to 6.45). Hyperglycemia and concurrent hyperlactatemia were associated with increased mortality risk (OR = 3.96, 95% CI = 2.01 to 7.79), but hyperglycemia in the absence of simultaneous hyperlactatemia was not (OR = 0.78, 95% CI = 0.39 to 1.57).

CONCLUSIONS: In this cohort of septic adult nondiabetic patients, mortality risk did not increase with hyperglycemia unless associated with simultaneous hyperlactatemia. The previously reported association of hyperglycemia with mortality in nondiabetic sepsis may be due to the association of hyperglycemia with hyperlactatemia.

What’s with all the chloride? An assault on salt

I continue to be bewildered at my ED colleagues’ overwhelming preference for 0.9% saline as a resuscitation fluid regardless of clinical presentation. However, I have to acknowledge a lack of robust high level clinical evidence demonstrating its relative harm compared with more balanced solutions such as Hartmann’s / Ringer’s lactate or one of the more scarcely available Plasma-Lyte solutions.

Human and animal studies have demonstrated that saline exacerbates hyperchloraemia and metabolic acidosis and has renal effects including renal vasoconstriction and decreased glomerular filtration rate. A large observational study on surgical patients suggested that saline therapy increases the risk of patients requiring acute dialysis compared with Plasma-Lyte administration(1).

A new study in JAMA provides some further clinical evidence that saline has harmful renal effects(2). It was a before-and-after observational study, in which the change was a restriction in chloride-rich fluids so that they were made available only after prescription by the attending specialist for specific conditions (eg, hyponatraemia, traumatic brain injury, and cerebral oedema). Four of the authors published another study on the metabolic effects of this changed fluid strategy, presumably on the same or an overlapping cohort of patients, which I blogged about here.

Significant findings were that the chloride-restrictive strategy was associated with a significantly lower increase in serum creatinine level during ICU stay, a decrease in the incidence of renal injury and failure (according to the RIFLE definitions), and a decrease in renal replacement therapy. These effects persisted after adjusting for known contributors to acute kidney injury.

As this is not a randomised trial cause and effect cannot be assumed, but this is consistent with other work.

In summary, keep pushing the saline if you want to increase your patients’ risk of acute kidney injury and the need for dialysis, whilst rendering them acidotic. You may even decrease their gut perfusion(3) and give them abdominal discomfort and subjective decreased cognitive ability(4). Alternatively, give Hartmann’s / Ringer’s lactate… although bear in mind that might not be such a good choice in the context of hyponatraemia, alkalaemia, cerebral oedema, or traumatic brain injury.

1. Major complications, mortality, and resource utilization after open abdominal surgery: 0.9% saline compared to Plasma-Lyte
Ann Surg. 2012 May;255(5):821-9


OBJECTIVE: To assess the association of 0.9% saline use versus a calcium-free physiologically balanced crystalloid solution with major morbidity and clinical resource use after abdominal surgery.

BACKGROUND: 0.9% saline, which results in a hyperchloremic acidosis after infusion, is frequently used to replace volume losses after major surgery.

METHODS: An observational study using the Premier Perspective Comparative Database was performed to evaluate adult patients undergoing major open abdominal surgery who received either 0.9% saline (30,994 patients) or a balanced crystalloid solution (926 patients) on the day of surgery. The primary outcome was major morbidity and secondary outcomes included minor complications and acidosis-related interventions. Outcomes were evaluated using multivariable logistic regression and propensity scoring models.

RESULTS: For the entire cohort, the in-hospital mortality was 5.6% in the saline group and 2.9% in the balanced group (P < 0.001). One or more major complications occurred in 33.7% of the saline group and 23% of the balanced group (P < 0.001). In the 3:1 propensity-matched sample, treatment with balanced fluid was associated with fewer complications (odds ratio 0.79; 95% confidence interval 0.66-0.97). Postoperative infection (P = 0.006), renal failure requiring dialysis (P < 0.001), blood transfusion (P < 0.001), electrolyte disturbance (P = 0.046), acidosis investigation (P < 0.001), and intervention (P = 0.02) were all more frequent in patients receiving 0.9% saline.

CONCLUSIONS: Among hospitals in the Premier Perspective Database, the use of a calcium-free balanced crystalloid for replacement of fluid losses on the day of major surgery was associated with less postoperative morbidity than 0.9% saline.

2. Association Between a Chloride-Liberal vs Chloride-Restrictive Intravenous Fluid Administration Strategy and Kidney Injury in Critically Ill Adults
JAMA. 2012 Oct 17;308(15):1566-72


CONTEXT: Administration of traditional chloride-liberal intravenous fluids may precipitate acute kidney injury (AKI).

OBJECTIVE: To assess the association of a chloride-restrictive (vs chloride-liberal) intravenous fluid strategy with AKI in critically ill patients.

DESIGN, SETTING, AND PATIENTS: Prospective, open-label, sequential period pilot study of 760 patients admitted consecutively to the intensive care unit (ICU) during the control period (February 18 to August 17, 2008) compared with 773 patients admitted consecutively during the intervention period (February 18 to August 17, 2009) at a university-affiliated hospital in Melbourne, Australia.

INTERVENTIONS: During the control period, patients received standard intravenous fluids. After a 6-month phase-out period (August 18, 2008, to February 17, 2009), any use of chloride-rich intravenous fluids (0.9% saline, 4% succinylated gelatin solution, or 4% albumin solution) was restricted to attending specialist approval only during the intervention period; patients instead received a lactated solution (Hartmann solution), a balanced solution (Plasma-Lyte 148), and chloride-poor 20% albumin.

MAIN OUTCOME MEASURES: The primary outcomes included increase from baseline to peak creatinine level in the ICU and incidence of AKI according to the risk, injury, failure, loss, end-stage (RIFLE) classification. Secondary post hoc analysis outcomes included the need for renal replacement therapy (RRT), length of stay in ICU and hospital, and survival.

RESULTS Chloride administration decreased by 144 504 mmol (from 694 to 496 mmol/patient) from the control period to the intervention period. Comparing the control period with the intervention period, the mean serum creatinine level increase while in the ICU was 22.6 μmol/L (95% CI, 17.5-27.7 μmol/L) vs 14.8 μmol/L (95% CI, 9.8-19.9 μmol/L) (P = .03), the incidence of injury and failure class of RIFLE-defined AKI was 14% (95% CI, 11%-16%; n = 105) vs 8.4% (95% CI, 6.4%-10%; n = 65) (P < .001), and the use of RRT was 10% (95% CI, 8.1%-12%; n = 78) vs 6.3% (95% CI, 4.6%-8.1%; n = 49) (P = .005). After adjustment for covariates, this association remained for incidence of injury and failure class of RIFLE-defined AKI (odds ratio, 0.52 [95% CI, 0.37-0.75]; P < .001) and use of RRT (odds ratio, 0.52 [95% CI, 0.33-0.81]; P = .004). There were no differences in hospital mortality, hospital or ICU length of stay, or need for RRT after hospital discharge.


CONCLUSION The implementation of a chloride-restrictive strategy in a tertiary ICU was associated with a significant decrease in the incidence of AKI and use of RRT.

3. The effects of balanced versus saline-based hetastarch and crystalloid solutions on acid-base and electrolyte status and gastric mucosal perfusion in elderly surgical patients
Anesth Analg. 2001 Oct;93(4):811-6
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The IV administration of sodium chloride solutions may produce a metabolic acidosis and gastrointestinal dysfunction. We designed this trial to determine whether, in elderly surgical patients, crystalloid and colloid solutions with a more physiologically balanced electrolyte formulation, such as Hartmann’s solution and Hextend, can provide a superior metabolic environment and improved indices of organ perfusion when compared with saline-based fluids. Forty-seven elderly patients undergoing major surgery were randomly allocated to one of two study groups. Patients in the Balanced Fluid group received an intraoperative fluid regimen that consisted of Hartmann’s solution and 6% hetastarch in balanced electrolyte and glucose injection (Hextend). Patients in the Saline group were given 0.9% sodium chloride solution and 6% hetastarch in 0.9% sodium chloride solution (Hespan). Biochemical indices and acid-base balance were determined. Gastric tonometry was used as a reflection of splanchnic perfusion. Postoperative chloride levels demonstrated a larger increase in the Saline group than the Balanced Fluid group (9.8 vs 3.3 mmol/L, P = 0.0001). Postoperative standard base excess showed a larger decline in the Saline group than the Balanced Fluid group (-5.5 vs -0.9 mmol/L, P = 0.0001). Two-thirds of patients in the Saline group, but none in the Balanced Fluid group, developed postoperative hyperchloremic metabolic acidosis (P = 0.0001). Gastric tonometry indicated a larger increase in the CO2 gap during surgery in the Saline group compared with the Balanced Fluid group (1.7 vs 0.9 kPa, P = 0.0394). In this study, the use of balanced crystalloid and colloid solutions in elderly surgical patients prevented the development of hyperchloremic metabolic acidosis and resulted in improved gastric mucosal perfusion when compared with saline-based solutions.
IMPLICATIONS: This prospective, randomized, blinded trial showed that, in elderly surgical patients, the use of balanced IV solutions can prevent the development of hyperchloremic metabolic acidosis and provide better gastric mucosal perfusion compared with saline-based fluids.

4. The effect of intravenous lactated Ringer’s solution versus 0.9% sodium chloride solution on serum osmolality in human volunteers.
Anesth Analg. 1999 May;88(5):999-1003
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Animal studies have shown that large volumes of IV lactated Ringer’s solution (LR) decrease serum osmolality, thereby increasing cerebral water. These studies have led to recommendations to limit LR to avoid cerebral edema in neurosurgical patients. Eighteen healthy human volunteers aged 20-48 yr received 50 mL/kg LR over 1 h on one occasion and 0.9% sodium chloride (NS) on another. Venous samples were taken at baseline (T1), at infusion end (T2), and 1 h after T2 (T3). Time until first urination was noted. With LR, serum osmolality decreased by 4+/-3 mOsm/kg from T1 to T2 and increased insignificantly with NS. At T3, osmolality returned almost to baseline in the LR group. Blood pH increased from T1 to T2 with LR by 0.04+/-0.04 and decreased with NS by 0.04+/-0.04. These pH changes persisted at T3. Subjective mental changes occurred only with NS. Abdominal discomfort was more common with NS. Time until first urination was longer with NS (106+/-11 min) than with LR (75+/-10 min) (P < 0.001). In healthy humans, an infusion of large volumes of LR, but not NS, transiently decreased serum osmolality, whereas acidosis associated with NS persisted and urinary output was slower with NS.


IMPLICATIONS: Large volumes of lactated Ringer’s solution administered to healthy humans produced small transient changes in serum osmolality. Large volumes of sodium chloride did not change osmolality but resulted in lower pH.

More on the meaning of lactate values

A newly published study(1) reminds us that we need to do better than just identify a raised lactate in patients with sepsis; we need to make sure it’s not increasing when they leave the ED (if we can). An incremental rise is associated with mortality.

The authors comment:


We found that the prognostic value of lactate continues to rise across a wide range of values, from 0 to 20 mmol/L…. These data suggest that grouping patients into less granular and larger groups, such as low, intermediate, and high, potentially underutilizes the prognostic value of the test. Furthermore, we did not find any value of lactate, up to a maximum value of 20 mmol/L, where mortality failed to increase with an increase in lactate concentration.

The paper does not state whether the lactate was arterial or venous, although either can be used. The Surviving Sepsis Campaign provides this comment:


In the course of the Campaign the question has been raised many times as to whether an arterial or venous lactate sample is appropriate. While there is no consensus of settled literature on this question, an elevated lactate of any variety is typically abnormal, although this may be influenced by other conditions..

This relationship between lactate trend and mortality has also been demonstrated in a study of all patients admitted to hospital (with or without sepsis), which also showed good correlation between arterial and venous lactate(2).

Lactate clearance has been shown to be an acceptable alternative to central venous oxygen saturation as a goal for therapy in ED severe sepsis patients(3), which is good because it provides one less reason for a central line.

Always remember the good emergency physician / critical care practitioner will consider other causes of a raised lactate, particularly when things don’t add up. I invented the ‘LACTATES’ acronym to help me remember them(4), and it’s come in handy several times.

Craving more info on lactate? Check out the EMCrit site with its great lactate reference sheet.

1. Prognostic Value of Incremental Lactate Elevations in Emergency Department Patients With Suspected Infection
Acad Emerg Med. 2012 Aug;19(8):983-5


Objectives:  Previous studies have confirmed the prognostic significance of lactate concentrations categorized into groups (low, intermediate, high) among emergency department (ED) patients with suspected infection. Although the relationship between lactate concentrations categorized into groups and mortality appears to be linear, the relationship between lactate as a continuous measurement and mortality is uncertain. This study sought to evaluate the association between blood lactate concentrations along an incremental continuum up to a maximum value of 20 mmol/L and mortality.

Methods:  This was a retrospective cohort analysis of adult ED patients with suspected infection from a large urban ED during 2007–2010. Inclusion criteria were suspected infection evidenced by administration of antibiotics in the ED and measurement of whole blood lactate in the ED. The primary outcome was in-hospital mortality. Logistic and polynomial regression were used to model the relationship between lactate concentration and mortality.

Results:  A total of 2,596 patients met inclusion criteria and were analyzed. The initial median lactate concentration was 2.1 mmol/L (interquartile range [IQR] = 1.3 to 3.3 mmol/L) and the overall mortality rate was 14.4%. In the cohort, 459 patients (17.6%) had initial lactate levels >4 mmol/L. Mortality continued to rise across the continuum of incremental elevations, from 6% for lactate <1.0 mmol/L up to 39% for lactate 19–20 mmol/L. Polynomial regression analysis showed a strong curvilinear correlation between lactate and mortality (R = 0.72, p < 0.0001).


Conclusions:  In ED patients with suspected infection, we found a curvilinear relationship between incremental elevations in lactate concentration and mortality. These data support the use of lactate as a continuous variable rather than a categorical variable for prognostic purposes.

2. Blood lactate as a predictor for in-hospital mortality in patients admitted acutely to hospital: a systematic review
Scand J Trauma Resusc Emerg Med. 2011 Dec 28;19:74 Free Full Text


BACKGROUND: Using blood lactate monitoring for risk assessment in the critically ill patient remains controversial. Some of the discrepancy is due to uncertainty regarding the appropriate reference interval, and whether to perform a single lactate measurement as a screening method at admission to the hospital, or serial lactate measurements. Furthermore there is no consensus whether the sample should be drawn from arterial, peripheral venous, or capillary blood. The aim of this review was: 1) To examine whether blood lactate levels are predictive for in-hospital mortality in patients in the acute setting, i.e. patients assessed pre-hospitally, in the trauma centre, emergency department, or intensive care unit. 2) To examine the agreement between arterial, peripheral venous, and capillary blood lactate levels in patients in the acute setting.

METHODS: We performed a systematic search using PubMed, Cochrane Central Register of Controlled Trials, Cochrane Database of Systematic Reviews, and CINAHL up to April 2011. 66 articles were considered potentially relevant and evaluated in full text, of these ultimately 33 articles were selected.

RESULTS AND CONCLUSION: The literature reviewed supported blood lactate monitoring as being useful for risk assessment in patients admitted acutely to hospital, and especially the trend, achieved by serial lactate sampling, is valuable in predicting in-hospital mortality. All patients with a lactate at admission above 2.5 mM should be closely monitored for signs of deterioration, but patients with even lower lactate levels should be considered for serial lactate monitoring. The correlation between lactate levels in arterial and venous blood was found to be acceptable, and venous sampling should therefore be encouraged, as the risk and inconvenience for this procedure is minimal for the patient. The relevance of lactate guided therapy has to be supported by more studies.

3. Lactate clearance vs central venous oxygen saturation as goals of early sepsis therapy: a randomized clinical trial
JAMA. 2010 Feb 24;303(8):739-46


CONTEXT: Goal-directed resuscitation for severe sepsis and septic shock has been reported to reduce mortality when applied in the emergency department.

OBJECTIVE: To test the hypothesis of noninferiority between lactate clearance and central venous oxygen saturation (ScvO2) as goals of early sepsis resuscitation.

DESIGN, SETTING, AND PATIENTS: Multicenter randomized, noninferiority trial involving patients with severe sepsis and evidence of hypoperfusion or septic shock who were admitted to the emergency department from January 2007 to January 2009 at 1 of 3 participating US urban hospitals.

INTERVENTIONS: We randomly assigned patients to 1 of 2 resuscitation protocols. The ScvO2 group was resuscitated to normalize central venous pressure, mean arterial pressure, and ScvO2 of at least 70%; and the lactate clearance group was resuscitated to normalize central venous pressure, mean arterial pressure, and lactate clearance of at least 10%. The study protocol was continued until all goals were achieved or for up to 6 hours. Clinicians who subsequently assumed the care of the patients were blinded to the treatment assignment.

MAIN OUTCOME MEASURE: The primary outcome was absolute in-hospital mortality rate; the noninferiority threshold was set at Delta equal to -10%.

RESULTS: Of the 300 patients enrolled, 150 were assigned to each group and patients were well matched by demographic, comorbidities, and physiological features. There were no differences in treatments administered during the initial 72 hours of hospitalization. Thirty-four patients (23%) in the ScvO2 group died while in the hospital (95% confidence interval [CI], 17%-30%) compared with 25 (17%; 95% CI, 11%-24%) in the lactate clearance group. This observed difference between mortality rates did not reach the predefined -10% threshold (intent-to-treat analysis: 95% CI for the 6% difference, -3% to 15%). There were no differences in treatment-related adverse events between the groups.

CONCLUSION: Among patients with septic shock who were treated to normalize central venous and mean arterial pressure, additional management to normalize lactate clearance compared with management to normalize ScvO2 did not result in significantly different in-hospital mortality.

4. Non-septic hyperlactataemia in the emergency department
Emerg Med J. 2010 May;27(5):411-2

Hypotonic Versus Isotonic Fluids After Surgery for Children

Kids in hospital with injury, infection or other illness, and those undergoing the physiological stress of surgery, produce (appropriately) elevated antidiuretic hormone levels which contribute to the risk of hyponatraemia by impairing free water excretion in the kidney.

Deaths have occurred on general paediatric and surgery wards when fluid regimens containing low concentrations of sodium (classically 0.18% or 0.225% NaCl) have resulted in hyponatraemia in children without adequate electrolyte monitoring, leading some bodies to recommend at least 0.45% NaCl solutions for maintenance fluid therapy in children.

However two recent studies1,2 on postoperative children show an increased risk of hyponatraemia even with 0.45% saline, when compared with 0.9% saline or Hartmann’s solution (Hartmann’s is similar – almost identical – to Ringer’s lactate).

I like the fact that paediatricians used Hartmann’s in one of these studies1. I have worked with several paediatricians who never use Hartmann’s, either from lack of experience or because of concern about its lactate content (not appreciating the lactate is metabolised by the liver to bicarbonate).
This is ironic, since Alexis Hartmann (1898–1964) was a paediatrician.

Want more fluid therapy irony? The ‘balanced salt solution’ used by Brits and Australasians is Hartmann’s solution – named after an American. The one used by Americans is Lactated Ringer’s solution – named after the British physician Sydney Ringer (1834-1910).

Medical history enthusiasts can read more about Hartmann and Ringer here.

1. A randomised controlled trial of Hartmann’s solution versus half normal saline in postoperative paediatric spinal instrumentation and craniotomy patients.
Arch Dis Child. 2012 Jun;97(6):491-6


OBJECTIVE: To compare the difference in plasma sodium at 16-18 h following major surgery in children who were prescribed either Hartmann’s and 5% dextrose or 0.45% saline and 5% dextrose.

DESIGN: A prospective, randomised, open label study.

SETTING: The paediatric intensive care unit (650 admissions per annum) in a tertiary children’s hospital in Brisbane, Australia.

PATIENTS: The study group comprised 82 children undergoing spinal instrumentation, craniotomy for brain tumour resection, or cranial vault remodelling.

INTERVENTIONS: Patients received either Hartmann’s and 5% dextrose at full maintenance rate or 0.45% saline and 5% dextrose at two-thirds maintenance rate.

MAIN OUTCOMES MEASURES: Primary outcome measure: plasma sodium at 16-18 h postoperatively; secondary outcome measure: number of fluid boluses administered.

RESULTS: Mean postoperative plasma sodium levels of children receiving 0.45% saline and 5% dextrose were 1.4 mmol/l (95% CI 0.4 to 2.5) lower than those receiving Hartmann’s and 5% dextrose (p=0.008). In the 0.45% saline group, seven patients (18%) became hyponatraemic (Na <135 mmol/l) at 16-18 h postoperatively; in the Hartmann’s group no patient became hyponatraemic (p=0.01). No child in either fluid group became hypernatraemic.

CONCLUSIONS: The postoperative fall in plasma sodium was smaller in children who received Hartmann’s and 5% dextrose compared to those who received 0.45% saline and 5% dextrose. It is suggested that Hartmann’s and 5% dextrose should be administered at full maintenance rate postoperatively to children who have undergone major surgery in preference to hypotonic fluids.

2. Hypotonic versus isotonic maintenance fluids after surgery for children: a randomized controlled trial
Pediatrics. 2011 Nov;128(5):857-66.


OBJECTIVE: The objective of this randomized controlled trial was to evaluate the risk of hyponatremia following administration of a isotonic (0.9% saline) compared to a hypotonic (0.45% saline) parenteral maintenance solution (PMS) for 48 hours to postoperative pediatric patients.

METHODS: Surgical patients 6 months to 16 years of age with an expected postoperative stay of >24 hours were eligible. Patients with an uncorrected baseline plasma sodium level abnormality, hemodynamic instability, chronic diuretic use, previous enrollment, and those for whom either hypotonic PMS or isotonic PMS was considered contraindicated or necessary, were excluded. A fully blinded randomized controlled trial was performed. The primary outcome was acute hyponatremia. Secondary outcomes included severe hyponatremia, hypernatremia, adverse events attributable to acute plasma sodium level changes, and antidiuretic hormone levels.

RESULTS: A total of 258 patients were enrolled and assigned randomly to receive hypotonic PMS (N = 130) or isotonic PMS (N = 128). Baseline characteristics were similar for the 2 groups. Hypotonic PMS significantly increased the risk of hyponatremia, compared with isotonic PMS (40.8% vs 22.7%; relative risk: 1.82 [95% confidence interval: 1.21-2.74]; P = .004). Admission to the pediatric critical care unit was not an independent risk factor for the development of hyponatremia. Isotonic PMS did not increase the risk of hypernatremia (relative risk: 1.30 [95% confidence interval: 0.30-5.59]; P = .722). Antidiuretic hormone levels and adverse events were not significantly different between the groups.

CONCLUSION: Hypotonic Versus Isotonic Maintenance Fluids After Surgery for Children: A Randomized Controlled Trial.

Fluids contribute to acid-base disturbance on ICU

Image from Wikipedia
I enjoyed a paper from Critical Care Medicine this month which relates to a major bugbear of mine: the prescription of 0.9% saline for critically ill patients and the consequent metabolic acidosis this causes. However it did produce some interesting findings that helped me review my own biases here.

In short, an ICU team decided to reduce and where possible eliminate the use of high chloride fluids including 0.9% saline and Gelofusine and replace with lower chloride fluids, mainly Ringer’s Lactate (Hartmann’s solution).

It is known that saline causes a metabolic acidosis by elevating chloride and reducing the strong ion difference. This results in a normal anion gap, hyperchloraemic acidosis. The clinical significance of this is uncertain, but the iatrogenic acidosis is often confused by clinicians as a sign of severe illness, especially those clinicians that don’t look at the chloride or anion gap.

Not surprisingly, changing the fluid policy resulted in less acidosis (and also less hypernatraemia). There was however an increase in severe alkalaemia. The study was not designed to look at patient oriented outcomes.

My observations are:

  • This is an important reminder that saline causes acidosis
  • Because of the possibility of worsening alkalosis, fluid therapy choice should be individualised for an ICU patient based on their known acid-base issues; in some cases, saline may be appropriate.
  • These patients were managed for several days on an ICU. Alkalaemia is common on the ICU for reasons that include hypoalbuminaemia, furosemide use, and iatrogenic hyperventilation. These factors are less relevant in the ED resuscitation population where such a degree of alkalaemia is rarely seen.
  • The authors point out that their results are “consistent with previous acute treatment studies, which were conducted in the perioperative or experimental setting” – isn’t it a shame that ED-based studies are not forthcoming?

The authors point to an additional finding:



Furthermore, our results suggest that routine use of lactate fluids such as Hartmann’s or Ringer’s lactate is associated with a detectable iatrogenic increase in lactate in the first 48 hrs after ICU admission, when, presumably, lactate clearance is less effective.


While this is interesting, the mean [SD] lactate values in the two groups were 1.79 [1.57] and 2.05 [1.61] so while statistically significant I suspect this is clinically irrelevant. And as we know, the cause of a raised lactate is more of a concern than the fact of a raised lactate

A significant benefit of the change in fluid policy was a signficant cost saving, largely due to the omission of Gelofusine.

For me, this study reassures me that my current practice of preferring Ringer’s Lactate to Saline in the resuscitation setting is likely to minimise iatrogenic acidosis without significantly elevating the lactate, in a population rarely afflicted by significant alkalaemia.

The biochemical effects of restricting chloride-rich fluids in intensive care
Crit Care Med. 2011 Nov;39(11):2419-2424




Objective: To determine the biochemical effects of restricting the use of chloride-rich intravenous fluids in critically ill patients.


Design: Prospective, open-label, before-and-after study.


Setting: University-affiliated intensive care unit.


Patients: A cohort of 828 consecutive patients admitted over 6 months from February 2008 and cohort of 816 consecutive patients admitted over 6 months from February 2009.


Interventions: We collected biochemical and fluid use data during standard practice without clinician awareness. After a 6-month period of education and preparation, we restricted the use of chloride-rich fluids (0.9% saline [Baxter, Sydney, Australia], Gelofusine [BBraun, Melsungen, Germany], and Albumex 4 [CSL Bioplasma, Melbourne, Australia]) in the intensive care unit and made them available only on specific intensive care unit specialist prescription.


Measurements and Main Results: Saline prescription decreased from 2411 L in the control group to 52 L in the intervention group (p < .001), Gelofusine from 538 to 0 L (p < .001), and Albumex 4 from 269 to 80 L (p < .001). As expected, Hartmann’s lactated solution prescription increased from 469 to 3205 L (p < .001), Plasma-Lyte from 65 to 160 L (p < .05), and chloride-poor Albumex 20 from 87 to 268 L (p < .001). After intervention, the incidence of severe metabolic acidosis (standard base excess5 mEq/L) and alkalemia (pH >7.5) with an increase from 25.4% to 32.8% and 10.5% to 14.7%, respectively (p < .001). The time-weighted mean chloride level decreased from 104.9 ± 4.9 to 102.5 ± 4.6 mmol/L (p < .001), whereas the time-weighted mean standard base excess increased from 0.5 ± 4.5 to 1.8 ± 4.7 mmol/L (p < .001), mean bicarbonate from 25.3 ± 4.0 to 26.4 ± 4.1 mmol/L (p < .001) and mean pH from 7.40 ± 0.06 to 7.42 ± 0.06 (p < .001). Overall fluid costs decreased from $15,077 (U.S.) to $3,915.


Conclusions: In a tertiary intensive care unit in Australia, restricting the use of chloride-rich fluids significantly affected electrolyte and acid-base status. The choice of fluids significantly modulates acid-base status in critically ill patients.


Salicylate poisoning and pseudohyperchloraemia

Severe salicylate poisoning can cause metabolic acidosis from an accumulation of salicylic acid, lactic acid, and ketone bodies. A high anion gap acidosis is therefore the typical metabolic abnormality seen. A case series illustrates salicylate poisoning presenting with a normal gap (hyperchloraemic) acidosis – one patient had a chloride of 111 mmol/l and the other 123 mmol/l. This can occur when some analysers falsely read an elevated chloride in the presence of high concentrations of salicylate.



Severe salicylate poisoning is classically associated with an anion gap metabolic acidosis. However, high serum salicylate levels can cause false increase of laboratory chloride results on some analyzers. We present 2 cases of life-threatening salicylate poisoning with an apparently normal anion gap caused by an important laboratory interference. These cases highlight that the diagnosis of severe salicylism must be considered in all patients presenting with metabolic acidosis, even in the absence of an increased anion gap.


Falsely Normal Anion Gap in Severe Salicylate Poisoning Caused by Laboratory Interference
Ann Emerg Med. 2011 Sep;58(3):280-1

What do I do with a high sensitivity troponin?

Newer high-sensitivity troponin tests can be positive in patients who would have negative tests with the ‘traditional’ assay, which can result in confusion about what to do with the patient, particularly those patients without an obvious cardiac presentation. A recent study1 shows that the majority of patients that fall into this group had non-cardiac discharge diagnoses.



Background: High sensitivity troponin T (hsTnT) detects lower levels of troponin T with greater precision than the 4th generation (cTnT) assay. However, the clinical implications of this are uncertain.


Objectives: Primary: Describe the proportion of patients who test ‘positive’ with hsTnT but negative with cTnT. Secondary: Determine proportion in each group with an adverse event (representation, AMI or died) within 90 days of the index test.


Method: 161 patients samples were tested with cTnT and hsTNT assays. McNemar’s test was used to compare paired samples. Electronic medical records were reviewed, with discharge diagnosis and 90 day outcomes determined blind to hsTnT results. Patients were then classified as ‘TnT negative’ (hsTnT was <0.014 mcg/mL), 'new positive' (hsTnT was ≥0.014 mcg/mL and cTnT <0.03 mcg/mL) and 'TnT positive' (cTNT was ≥0.03 mcg/mL)


Results: Positive results more than doubled with the hsTnT assay (50% vs 22%, P < 0.001). 81 patients were ‘TnT negative’, 44 were ‘new positive’ and 36 ‘cTnT positive’. The discharge diagnosis for ‘new positives’ was AMI in 4 (9%), other cardiac in 13 (30%) and non-cardiac in 27 (61%). At 90 days adverse events occurred in 30%, 54% and 50% of the groups respectively. There were no late cases of AMI or cardiovascular death in ‘new positive’ patients.


Conclusion: Many patients with diagnoses other than AMI will have hsTNT above the reference level. Indiscriminate testing with hsTnT might lead to more patients requiring serial troponin testing and/or invasive further tests, which will have process and resource implications for EDs and health services.


An accompanying editorial2 highlights that:

Elevations are seen in pathological conditions, including structural heart disease, renal impairment and pulmonary embolism, but might also be seen in extreme exertion, such as marathon runners. It is now clear that when using a highly sensitive assay, circulating levels of troponin will be detected in many normal people.

The editorial makes the interesting observation that the duration of rise may help elucidate the cause; ischaemic elevation of troponin falls rapidly, since the rise might be due to the release of small amounts of troponin that exist free within the cytoplasm, in contrast to the more persistent elevation seen with myocardial necrosis. The editorialist provides the following caution:


Overall, our practice for ordering troponin will need to be urgently reviewed. Single troponin values will continue to be of little to no use in defining disease states in the ED. Identifying a chronic versus an acute elevation will only be revealed by serial troponin testing. The time interval between testing is currently contentious.

High sensitivity troponins are referred to in the newly published 2011 Addendum to the National Heart Foundation of Australia/Cardiac Society of Australia and New Zealand Guidelines for the Management of Acute Coronary Syndromes (full text link below)3:

RECOMMENDED PROTOCOL FOR TROPONIN TESTING USING HIGH SENSITIVITY ASSAYS IN “RULING-OUT” ACS
  • All patients with a suspected ACS should undergo troponin testing on arrival at ED to ‘rule in’ ACS within the differential diagnosis
  • For a patient with a positive troponin result or a change in troponin levels over time, neither ACS nor other significant pathology (e.g. pulmonary embolus, aortic dissection, and sepsis) can be excluded. These patients are at higher risk of subsequent events. A positive result should be considered within the entire clinical context (history, examination, ECG findings and other investigations). Further investigations directed at all plausible clinical diagnoses should be considered and, if ACS is thought to be the likely cause, these patients may require cardiology assessment.
  • All patients with a negative result should undergo repeat testing 3–4 hours later.
  • The testing interval to ‘rule out’ MI may be reduced to 3 hours, provided that one sample is taken at least 6 hours after symptom onset:
  • Patients with a negative result at 3 hours after presentation and at least 6 hours after the onset of pain should be considered for early assessment by non-invasive anatomic or functional testing, as determined by local availability.
  • For patients presenting more than 6 hours after pain onset, a single high sensitivity troponin assay is sufficient to rule out myocardial infarction in the absence of ongoing chest pain.

High sensitivity troponin assays have an increased sensitivity for the detection of “myonecrosis”, but a reduced specificity for the diagnosis of “MI”. A positive result (≥99th centile for reference population OR where there is a change of ≥50% above an initial baseline level) should be interpreted in the context of the entire clinical presentation and does not necessarily represent an indication for coronary angiography. The management MI secondary to other conditions (e.g. anaemia, thyrotoxicosis, and sepsis) should be primarily directed at those conditions.
The finding of troponin concentrations that remain stable over time suggests that the presence of troponin is due to chronic disease. Acute exacerbations of chronic disease that result in elevated troponin levels can mimic an MI release pattern.

1. Clinical diagnosis and outcomes for Troponin T ‘positive’ patients assessed by a high sensitivity compared with a 4th generation assay
Emerg Med Australas. 2011 Aug;23(4):490-501

2. Troponin: A risk-defining biomarker for emergency department physicians
Emerg Med Australas. 2011 Aug;23(4):391-4

3. 2011 Addendum to the National Heart Foundation of Australia/Cardiac Society of Australia and New Zealand Guidelines for the Management of Acute Coronary Syndromes
Heart, Lung and Circulation 2011 Aug;28(8):487-502 Free Full Text

Hyperkalaemia dogmalysis


One of the things I enjoy most is the dismantling of medical dogma. In his brilliant blog Precious Bodily Fluids, nephrologist Joel Topf reviewed some of the hyperkalaemia literature and offers some of the following pearls:

  • The ECG is insensitive and non-specific as a means of diagnosing (and in particular ruling out) hyperkalaemia (sensitivity of ‘strict’ criteria of symmetrical peaked T waves that resolve on follow up: 18%; sensitivity of any ECG change: 52%).
  • The dangers of calcium treatment for digoxin toxicity-associated hyperkalaemia may be exaggerated and are supported by very weak evidence
  • Sodium bicarbonate does not effectively lower potassium but does lower ionised calcium which can increase the risk of hyperkalaemia-associated dysrhythmia

Read the full blog post here

View Dr Topf’s presentation below: