Category Archives: Fluids

SOLAR trial – Saline vs Lactated Ringers’

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solar trialThe SOLAR trial, which compared a composite outcomes in perioperative colorectal or orthopaedic patients, assigned to Lactated Ringers’ (similar to Hartmann’s) solution – over 2 week blocks over a few years (8,616), has been published this month in Anesthesiology. The median volume of fluid administered in the perioperative period was 1.9L, and, no surprise here – there was no difference in outcomes.

Here is the blurb from the abstract:

“Among 8,616 qualifying patients, 4,187 (49%) were assigned to lactated Ringer’s solution, and 4,429 (51%) were assigned to saline. Each group received a median 1.9 l of fluid. The primary composite of major complications was observed in 5.8% of lactated Ringer’s versus 6.1% of normal saline patients, with estimated average relative risk across the components of the composite of 1.16 (95% CI, 0.89 to 1.52; P = 0.261). The secondary outcome, postoperative acute kidney injury, Acute Kidney Injury Network stage I–III versus 0, occurred in 6.6% of lactated Ringer’s patients versus 6.2% of normal saline patients, with an estimated relative risk of 1.18 (99.3% CI, 0.99 to 1.41; P = 0.009, significance criterion of 0.007). Absolute differences between the treatment groups for each outcome were less than 0.5%, an amount that is not clinically meaningful.”

The two litres of Saline / LR did not cause acidosis or meaningful increase in plasma chloride concentrations at 24 hours – chloride rose in both groups initially and then fell off. If the median volume of fluid was 2L – then there was a median difference in chloride intake of 80mmol – roughly what is in half a litre of saline. There is good reason to believe that hyperchloraemic fluids (such as LR and Saline) in lowish volume (2L) don’t change acid base status, due to dilution of albumin and then clearance.  It would have been really helpful to know what, if any, iv fluid was given post op and how much sodium and chloride the patients received over the 3 days of the stress response.

These results differ from the SMART-MED and SALT-ED trials – which despite extraordinarily small volumes of fluid, purported to show an increase in complications – particularly renal with saline. Presumably, critically ill and emergency room patients are at greater risk for organ dysfunction, and the additional sodium and chloride pushed a few “over the edge.”

An impressive study that shows that any anaesthesia department can do important research just by altering one component of “what we always do” every couple of weeks and then looking at outcomes from a largish cohort. It won’t change my practice, and I would dearly have liked to see the study done with plasmalyte-148 rather than LR.

Transfusion Strategy – Think Restrictive

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nejm_transf_1.2013A half generation ago, the TRICC trial (here) suggested that routine blood transfusion in critically ill patients did not confer benefit if the haemoglobin level was above 7g/dl. This resulted in a evidence based paradigm for lower transfusion triggers. The problem was – how do you deal with the bleeding patients?
A recent study in NEJM (here) looked at liberal versus restrictive transfusion practices on patients admitted with gastrointestinal bleeding.

921 patients with severe acute upper gastrointestinal bleeding were included in the study: and 461 of them were randomly assigned to a restrictive strategy (transfusion when the hemoglobin level fell below 7 g per deciliter) and 460 to a liberal strategy (transfusion when the hemoglobin fell below 9 g per deciliter). Randomisation was stratified according to the presence or absence of hepatic cirrhosis.

Substantially more patients in the liberal strategy group received transfusion: 395 (85%)  versus 236  (49%) liberal versus restrictive (P<0.001). The conventional wisdom would hold that greater oxygen carrying capacity in the liberal group would result in better outcomes. The null hypothesis would be that there was no difference. However, the patients in the restrictive group had BETTER OUTCOMES. The hazard ratio for 6 week mortality was 0.55; 95% confidence interval [CI], 0.33 to 0.92; P=0.02) [with HR a number of <1 reflects benefit, >1 reflects injury]. The absolute risk reduction was 4% (5% restrictive, 9% liberal p = 0.02; NNT 25). In addition, patients in the liberal strategy group had a 6% absolute increase (number needed to injure 16; (P=0.01) ) in the risk of further bleeding.
There was an absolute risk reduction of adverse events of 8% in the restrictive group (NNT 12; p = 0.02). Restrictive transfusion also resulted in better survival in patients with peptic (gastric or duodenal) ulcers, and those with mild to moderate cirrhosis.

Why would bleeding patients do better if transfusions are witheld? There are many potential reasons: 1. The concept of damage control resuscitation: teleologically we have evolved to handle hypovolaemia and can survive considerable blood loss. Blood transfusion without source control may cause clots to destabilise and further bleeding to occur. 2. Blood is immunosuppressive: patients who are transfused are at elevated risk of infectious complications. 3. In this particular study patients in the liberal transfusion group had higher portal pressures and were more likely to rebleed (but so too were patients with peptic ulcers). 4. Transfusion may result in volume overload, abdominal compartment syndrome, myocardial ischaemia and transfusion related lung injury.

What are the implications of this study. Approach with caution! This study does not license clinicians to withhold blood from ex-sanguinating patients. Nor does it prove anything about transfusion in the setting of non gastrointestinal blood loss. However, it does provide us with further information about the safety and implications of blood transfusion in a specific setting. Allied with accumulating data detailing the hazards of colloid transfusion, adverse outcomes associated with crystalloid over-resuscitation, and the ongoing controversy regarding albumin – one has to wonder where we are with fluid resuscitation. Remembering that red cell transfusion is a key component of the Rivers’ surviving sepsis protocol, one wonders if this is the first real nail in the coffin for that approach.

Comments are welcome here.

At last – Chloride is nephrotoxic

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For years I have been trotting around the world telling everyone that NaCl 0.9% is evil, because each litre delivers 50mmol of HCL and chloride is nephrotoxic. This belief has come from a series of studies in volunteers (reduced GFR, reduced splanchnic perfusion, reduced cortical blood flow) and observations (increased contrast nephropathy with NaCl versus NaHCO3. I suggested that the CHEST trial failed to prove that HES was dangerous because the control fluid was saline. But where was the real proof of nephrotoxicity.
Here it is in JAMA (click here).

A group in Melbourne, Australia, performed a sequential patient cohort study during 2 time periods: in phase 1 any IV fluid could be used; in phase 2 (the following year), chloride rich fluids were unavailable, so balanced salt solutions only could be prescribed.

Chloride administration fell considerably: from 694 to 496 mmol/patient from the control period to the intervention period. Patients in the chloride rich period had significantly worse renal outcomes: 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). In other words – patients given balanced chloride fluids had a 3.7% reduction in the risk of needing dialysis (NNT <30). As you would expect, there was no difference in mortality figures.

The accompanying editorial can be read here.

No I won’t do it and here is the proof!

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As a junior doctor how many times were you called to replace an iv catheter on a veinless patient because with was 3 days old (and “hospital policy” and all that). There was no point asking to see the evidence on which this “policy” was based. Whatever! – here is the counter evidence, and it is in the Lancet (here).

The study in question was a multicentre, randomised, non-blinded equivalence trial recruited adults (≥18 years) with an intravenous catheter of expected use longer than 4 days from three hospitals in Queensland, Australia in 2008-09 (why so long to publish?). There were 3283 patients randomised (5907 catheters- 1593 clinically indicated; 1690 routine replacement).

The mean time the iv cannulae lasted when they were in situ on day 3 was 99 h (SD 54) when replaced as clinically indicated and 70 h (13) when routinely replaced. In other words – not routinely changing the catheter resulted in it being in place for 1.25 extra days. Phlebitis occurred in 114 of 1593 (7%) patients in the clinically indicated group and in 114 of 1690 (7%) patients in the routine replacement group: ABSOLUTELY NO DIFFERENCE, NONE, STOP ASKING ME LEAVE ME ALONE!

So, if the iv site looks ok – it is ok. Don’t go prodding the patient.

Just when you thought it was unsafe….HES again!

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A couple of weeks ago I announced the imminent death of colloid. Now it’s back with another “Safe” trial (known as CHEST) from our colleagues in Australia and New Zealand (here). The study enrolled a colossal number of patients (7000) to either isotonic saline (IS) or Voluven (R). This is a 130/0.4 tetrastarch in isotonic saline. I now understand the kerfuffle over the 6s trial (of tetraspan) that mislabeled 130.42 in balanced salt as 130/0.4 (read here). The paper should be subtitled: “ours – the starch that doesn’t kill!” Perhaps…
The authors randomly assigned 7000 patients who had been admitted to an intensive care unit (ICU) in a 1:1 ratio to receive either 6% HES with a molecular weight of 130 kD and a molar substitution ratio of 0.4 (130/0.4, Voluven) in 0.9% sodium chloride or 0.9% sodium chloride (saline) for all fluid resuscitation until ICU discharge, death, or 90 days after randomization. The patients were permitted 50ml/kg HES per day and then were given saline. Similar to the SAFE (albumin) trial, clinicians were permitted to resuscitate patients according to their own goals and preferences.
The primary outcome was death within 90 days. Secondary outcomes included acute kidney injury and failure and treatment with renal-replacement therapy.
There was no mortality difference. A total of 597 of 3315 patients (18.0%) in the HES group and 566 of 3336 (17.0%) in the saline group died (relative risk in the HES group, 1.06; 95% confidence interval [CI], 0.96 to 1.18; P=0.26). There was no significant difference in mortality in six predefined subgroups. Renal-replacement therapy was used in 235 of 3352 patients (7.0%) in the HES group and 196 of 3375 (5.8%) in the saline group (relative risk, 1.21; 95% CI, 1.00 to 1.45; P=0.04).
HES was associated with less renal injury than saline, by RIFLE criteria, but post hoc creatinine and urinary output were worse for HES In the HES and saline groups, renal injury occurred in 34.6% and 38.0% of patients, respectively (P=0.005), and renal failure occurred in 10.4% and 9.2% of patients, respectively (P=0.12). There was a 1.2% absolute increase in the risk of needing renal replacement therapy (p<;0.5) in the HE’S group.
HES was associated with significantly more adverse events (5.3% vs. 2.8%, P<;0.001). These included itching, skin rash and “other” (not explained).

A few comments: the mortality rate for a critical care study was astonishingly low, suggesting that the addition of surgical patients (42%) and some entry restrictions may have biased the study [Of the 7000 patients 2,876 were admitted from the operating room]. Almost 10% of patients came from another hospital. Only 1 in 4 came from the emergency department. So there is likely lead-time bias (incidentally, this distribution is near identical to the 6S study. It is highly unlikely that the majority of patients received, exclusively, one of these investigation fluids prior to ICU admission. Patients were in the ICU for 10 or 11 hours prior to randomization: the “golden window”. The patients should have been resuscitated by this stage. This is suggested by the almost ludicrously small amount of fluid that patients received day 0 (see below).

As expected HES patients received less fluid early on, but this did not translate into better outcomes. What is surprising is how little fluid the patients received in the first 24 hours (1500ml to <;2000ml net fluid balance). Patients received between 1000ml (HES) and 1500ml (IS) in addition to study fluids. In fact they seem to have gotten a lot more non study fluid than study fluid. This is presumably due to the 50ml/kg limit (400ml for an 80kg patient). As the on study fluid of choice was IS, this was really a crystalloid plus colloid versus crystalloid study. Indeed patients almost exclusively received IS
It is remarkable how little fluid the patients accumulated over the first 3 days (by the end of day 3 the IS group appear to have a net negative balance). What ever way you look at it, patients received significantly less fluid than in the 6S study (nearly 6L day 1). I return to my previous observations: nearly 50% surgical patients, with resolving stress responses, patients probably already resuscitated before randomized to the study.

It would have useful to know the electrolyte and acid base status. These patients all received a lot of chloride: what proportion of the had hyperchloremic acidosis?

It is very hard to make anything of the renal function tests in this study. On first sight the 36% rate of renal dysfunction at baseline was similar to 6S. But Scandanavian patients were significantly sicker. They had a mortality rate of 43-50%, consistent with other sepsis trials (such as VISEP). RRT use in the 6S study was 16% in the Ringer’s acetate group versus 5.8% in the IS group in this study. So I would be inclined to ignore RIFLE numbers and consider “real” kidney injury to be represented by the need for RRT.

So, how to evaluate this study? Does this study demonstrate the safety of HES in critical illness? No, it just shows that HES doesn’t increase mortality versus isotonic saline. They may be equally bad. Does this paper conflict with the 6S study? Only 30% of patients in the study were septic, the mortality was substantially lower in this study and it is likely that HES worsens outcomes in patients that require more of it (i.e. sicker patients). The onus of proof is on the intervention: HES demonstrates no mortality advantage over crystalloid, it may worsen outcome, it may be associated with more organ (particularly kidney) dysfunction. I am less likely to use these products in ICU. However, there is still a small argument for colloid administration in the peri operative period based on a series of oesophageal Doppler studies (from the UK). It is highly unlikely that 500ml HE’S will harm a patient. However, I don’t quite see the point: HES is expensive compared with crystalloid and only appears to have a marginally better volume expanding effect: why take the risk without clear benefit.
I presume some clever scientist will take this, the 6S and other crystalloid-colloid studies and inform us about all of the residual questions in a nice meta-analysis. In the near future, it would be helpful if the CHEST investigators would give us data on chloride levels and acid-base status. Perhaps their next study should be to compare isotonic saline to balanced salt solutions.
Finally, congrats again to the ANZICS trial group for showing the rest of us what can be done.

Giving up Colloid? – Yes we can!

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Colloid lovers are distraught by the publication of the 6S study from Scandanavia, which has demonstrated that hydroxy ethyl starches (HES) were associated with poor outcomes (read here). For many of us, however, colloids are like nicotine, caffeine, carbohydrates and heroin rolled into one: we just believe in them. It’s so hard to stop. This month in Critical Care Medicine, a German hospital critical care group proved that you could – quit! (read here – subscription required)
In the Jena intensive care unit, over a 6 year period, clinicians initially used HES, gelatin and crystalloid, then gelatin and crystalloid and ultimately crystalloid only. Bayer and colleagues looked at CVP changes, SvO2, lactate normalisation, normalisation of MAP and discontinuation of vasopressors – comparing each phase against each other. In the first instance, CVP increased faster with colloids than crystalloids, which would be terrific if anyone had ever shown that rapidly increasing CVP improved outcomes. It doesn’t. In fact CVP is next to useless (if you don’t believe me – read this). Fluids are administered to reverse shock, and in each of the phases colloids had no appreciable benefit. Indeed, the amount colloid versus crystalloid was revealing: for HES it was 1:1.4 (HES vs Crystalloid i.e. 700ml Lactated Ringers versus 500ml HES 130/0.4); for gelatin it was 1:1.1 (i.e. 550ml LR versus 500ml gelatin). So there was little, if any, colloid effect. Moreover, patients in the crystalloid group mobilised fluid earlier than those in the colloid group.
So, colloids had no beneficial effect. What about harm? There was more acute kidney injury, worsened renal indices and longer continuous renal replacement therapy in the colloid group. Finally, patients who received colloids spent longer on mechanical ventilators than patients who received crystalloids.
It could be argued that this cohort study was flawed in that, as medicine advance, outcomes necessarily improve. So the newest patients should have had the best outcomes. However, there is no evidence that critical care outcomes are better now than 7 or 8 years ago, nor has the clinical practice move on significantly. From my perspective these data are valid, and may provide a roadmap to navigating ourselves away from the crutch and clutch of colloids.