SOLAR trial – Saline vs Lactated Ringers’

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.

Beachchair and Blood Pressure

BeachChairMAPIt is now more than 5 years since the Anesthesia Patient Safety Foundation highlighted the risk of central nervous system injury following anesthesia for shoulder surgery (SS) in the Beachchair position (BCP) (click here). Although we can never be certain, it appears likely that such injuries – principally devastating stroke, results from hypoperfusion and watershed ischaemia. Most anesthetists agree that, in the seated position, the mean arterial pressure as measured by a brachial cuff, under-estimates the pressure at the circle of Willis by 15mmHg or more. The safe lower range of MAP with regard to cerebral auto regulation remains unclear, but it is certainly not below 50mmHg (click here). Regardless, if we are to believe in the “Waterfall” effect of blood pressure, then a MAP of 65mHg from an arm BP cuff is marginal. If an arterial line is place – a procedure rarely performed in orthopedic shoulder patients – the transducer should be sited at the external auditory meatus. Although there are proponents for cerebral oximetry as a monitor in this setting – I do not believe that data are sufficient to demonstrate sensitivity and specificity of this device (here). The majority of experts in the field agree that the best option is to keep BP as close to baseline as possible if general anesthesia is administered for SS in BCP (here here and here). Clearly – “induced hypotension” is a bad idea in this setting. Also, the placement of the BP cuff on the leg or ankle (so that it does not cut of the iv line periodically) would appear most unwise. In one paper from Korea (click here), ankle blood pressure was substantially higher (up to 30mmHg for systolic pressure, 20mmHg mean pressure) compared with brachial pressure in the Beachchair position. In other words – if you are using an ankle cuff, the measured blood pressure (MAP) may be 35mmHg or more higher than the pressure seen at the circle of Willis.

My own practice is to use a brachial cuff and administer a phenylephrine infusion to keep the MAP above 75mmHg (or at the normal awake range for the patient). This appears to be the best approach based on my reading of the literature and available technologies. I would urge orthopedic anesthetists in the West to read the articles referenced here and come up with their own protocols. Comments?

Transfusion Strategy – Think Restrictive

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.

Troponin Leak Postop – what does it mean?

vision studyTwenty years ago perioperative myocardial ischaemia was a relatively easy thing to diagnose – we checked ECG looking for ST segment and T wave changes, and looked for an MB-CK rise. Then troponin arrived, and suddenly the proportion of patients with perioperative ischaemia increased drastically. For many of us, the report of a “postoperative troponin leak” results in a shoulder shrug: we don’t know what it means, we don’t really know the long term implications.

Thankfully, a landmark study, VISION (click here), has provided us with quality epidemiologic data. This was a cohort study of 15000 patients >45 years that underwent non cardiac surgery and had troponin T (TnT) measured in the first 3 postoperative days. All patients had to have procedures that required overnight stay in hospital. The main outcome measure was 30 day mortality.

After 30 days 1.9% of patients had died. Patients were more likely to die if their peak TnT level was 0.02 ng/ml (versus reference range of <0.01 ng/ml). This occurred in 11.6% of patients. The greater the TnT level, the more likely the patient was to die. They were able to stratify risk depending on TnT levels. Patients with a peak TnT value of 0.01 ng/mL or less, 0.02, 0.03-0.29, and 0.30 or greater had 30-day mortality rates of 1.0%, 4.0%, 9.3%, and 16.9%, respectively (figure above).

Risk was expressed in terms of Hazard Ratio (HR): greater HR = more likely adverse outcome with 1 being equivalent to no additional risk, <1 lower risk, >1 higher risk. Peak TnT of 0.02 ng/mL (adjusted hazard ratio [aHR], 2.41; 95% CI, 1.33-3.77); 0.03 to 0.29 ng/mL (aHR, 5.00; 95% CI, 3.72-6.76); and 0.30 ng/mL or greater (aHR, 10.48; 95% CI, 6.25-16.62).

Who was at increased risk? The older the patient the higher the risk. Emergency surgery, general surgery, neurosurgery were associated with increased risk. Vascular surgery was not, although the presence of peripheral vascular disease, COPD, previous stroke, coronary arterial disease and cancer did predict adverse outcome. Diabetes, obesity, afib, OSA, hypertension, orthopaedic/thoracic urology surgery – did not predict adverse events.

Conclusions: these data demonstrate the efficacy of TnT measurement in determining perioperative prognosis. 1in 25 patients with a peak TnT measurement of 0.02ng/mL,1 in11patients with a peak TnT measurement of 0.03 to 0.29ng/mL, and 1 in 6 patients with a peak TnT measurement of at least 0.30ng/mL will die within 30 days of surgery. Two questions arise from this study: 1. should we be routinely measuring TnT postoperatively in surgical inpatients >45 years; 2. If the patient has a troponin leak – what should be do then: PCI, aspirin, clopidogrel, statins, betablockers, all of the above, none of them? Will routine measurement of TnT result in a dramatic increase in cardiology consultations with little evidence that there are interventions that may improve outcomes in this setting?

Is it time to re-evaluate core concepts of Neuro-Intensive Care?

Over the past 2 or 3 decades a variety of technologies have been introduced into the clinical care of the brain injured patient – intraventricular ICP monitoring devices,SjVO2, brain tissue oxygen devices, microdialysis, xenon flow scanning, etc. However, compared with general critical care, the evidence base for protocols based on the utilization of these technologies is poor. There are 3 clinical approaches to managing the patient with traumatic brain injury – an ICP based strategy (the intracranial pressure is targeted at below 20mmhg), a CPP based strategy (cerebral perfusion pressure is targeted above 60mmhg = MAP-ICP) and an anti-adrenergic strategy (the “Lund” approach) that strives to reduce cytotoxic cerebral oedema by administering opioids, beta blockers etc. Many NICUs combine an ICP and a CPP strategy such that patients are administered vasopressors and osmotic diuretics simultaneously. To an outsider this is frequently puzzling, as the major cause or raised ICP is both cerebral oedema and increased blood flow. Hence there is a constant argument about hyperaemic versus hypoaemic brain injury – too much versus too little flow. How do you decide? Also, there is concern that ICP does not monitor global intracranial pressure, but merely a compartment pressure in that part of the brain in which the bolt or catheter has been inserted. Although it is claimed that ICP monitoring is a global standard of care for the management of the brain injured patient (TBI plus GCS<8), clearly this presumes that such patients are admitted to a hospital that can insert ICP measurement devices, and can cope with complications. However, as we are all very aware in Ireland, neurosurgery and neuro-trauma tends to be located in superspecialist centres, remote from where many trauma patients are initially admitted, and in our case – bed capacity in those centres is severely limited. Many patients with TBI are cared for in general ICUs in Ireland without ICP measurement devices. Anecdotally, they appear to be doing pretty well: could it be that ICP monitors don’t make a huge difference.

To do a study of ICP monitors in advanced healthcare systems would be problematic – how could you get IRB approval, in the USA, for example? Despite the appearance of equipoise of opinion, “standards are standards”. Of course, bleeding patients with fevers was a standard of 2,000 years. I had despaired whether or not a proper randomised controlled trial of ICP monitoring would be performed. No longer – here it is (click here pdf available here).

Chestnut and colleagues in this weeks NEJM noted: “The identification of a group of intensivists in Latin America who routinely managed severe traumatic brain injury without using available monitors and for whom there was equipoise regarding its efficacy eliminated that ethical constraint and led to the implementation of the randomized, controlled trial described here.” So, in Equador and Bolivia, the Benchmark Evidence from South American Trials: Treatment of Intracranial Pressure (BEST:TRIP) trial, was performed. The primary hypothesis was that “a management protocol based on the use of intracranial-pressure monitoring would result in reduced mortality and improved neuropsychological and functional recovery at 6 months. Our secondary hypothesis was that incorporating intracranial-pressure monitoring into the management of severe traumatic brain injury would have benefits for the health care system, including a reduced risk of complications and a shorter ICU stay.”

To be included in the study, patients had to be older than 13 and have a GCS of 3 8 at the time of enrollement. The study was a multicenter, parallel-group trial, with randomized assignment to intracranial-pressure monitoring (the pressure-monitoring group – ICP with and intraparenchymal bolt) or imaging and clinical examination (the imaging–clinical examination group – GEG ). Essentially, the control group were managed conservatively, scanned several times and examined carefully – protocol . 324 patient were enrolled and the study ran for 3 years.

“There was no significant between-group difference in the primary outcome, a composite measure based on percentile performance across 21 measures of functional and cognitive status (score, 56 in the pressure-monitoring group vs. 53 in the imaging–clinical examination group; P=0.49). There was no difference in 6 month mortality (39% in the ICP group and 41% in the control group (CEG) (P=0.60)). The median length of stay in the ICU was similar in the two groups (12 days in ICP and 9 days in the imaging–CEG; P=0.25). Although aftercare from TBI in these countries is clearly weak, and 6 month outcomes were relatively poor, 14 day outcomes were comparable with those in wealthy countries, and there was no difference between the groups at that stage either.

Surprisingly, the CEG group received more hypertonic saline, barbiturates and hyperventilation than the ICP group: I can’t quite figure out why – perhaps normal range ICP reassured that clinicians looking after those patients. The interventions in question were part of the protocol.

So, where does this leave us: is the ICP bolt the Swan Ganz catheter of the 2010s? Or does this study show that monitors do not improve outcomes, algorithms that use them appropriately do?

My own opinion – I believe this study at least casts doubt on arbitrary guidelines that continue to accumulate as a means of controlling clinicians clinical practice. It reinforces the importance of clinical examination alongside clinical monitoring, and emphasises the importance of having good doctors at the bedside looking at their patients (as opposed to the telemedicine concept of decision making based on measured data rather than clinical signs). It also emphasises the importance of not over sedating patients, and hence obliterating clinical signs, and slowing recovery. Is it the beginning of the end for ICP monitoring – unlikely, but at least it might row back a little on the “paint by numbers” approach to critical care that has become prevalent over the past decade or so.

The Toyota approach to anaesthesia- small continuous improvements: using placebo, IV cannulation, echo, blocks and compression devices

Toyota is famous for improving their cars through a process of continuous, small, incremental improvements, a technique known as Kaizen, or the Toyota way. In this way many small improvements, each inconsequential on their own, when added together produce significant results.

I think this is a great model to use when looking at anaesthesia. Anaesthesia and surgery are complicated processes, and most of the “low hanging fruit” in terms of safety improvements have already been made. It is unlikely that any single factor will make a major difference to outcomes. However that doesn’t mean we should stop trying to improve, and using a wide range of small improvements in different areas will collectively improve the patient’s experience.

An example of this is IV cannulation, something we all do every day and which we often forget can be quite painful. In addition, this is often patient’s only way of judging the ability of their anaesthetist. I recall a poster presentation where only 2 things determined a patients satisfaction with their anaesthetist- did the IV hurt, and did they visit the patient more than just in recovery. The patient has no baseline to judge postoperative pain or nausea and can awaken after all sorts of intraoperative near-catastrophes none the wiser, however if you want to make a patient happy, get the drip in first time and make sure it doesn’t hurt!

Two articles on this topic have got my attention and changed my practice. Both involve randomised trials where patients were either warned they were going to feel a “sharp sting” or used more neutral and comforting words, eg  “I am going to apply the tourniquet on the arm. As I do this many people find the arm becomes heavy, numb and tingly. This allows the drip to be placed more comfortably”. The patients not only reported lower pain scores but were also less likely to withdraw their hand in the “kind words” group compared to the “nocebo” group. This is contrary to the common practice of warning someone, with the rational that it then won’t be as bad as they expect. In fact all this achieves is heightened anxiety and more pain (read here and here).

This is an example of avoiding the “nocebo” (opposite of placebo) effect of harsh words like sharp, sting, needle and pain. There is increasing evidence that placebo plays a major part in many interventions. Recently i went to an intriguing talk about placebo where the concept of the “open/hidden” trial was discussed. This is the opposite to a placebo controlled trial. Instead of everyone getting told they were getting morphine and half getting a sugar pill, all patients get given morphine but only half are told about it. The rest had it quietly slipped into a bag of fluid without being told. There were significantly greater reductions in pain in the group that were told they were getting the “powerful painkiller”, compared to the group that had it slipped into their fluids. The presenter gave a range of slides for different analgesics showing that for virtually all of them the pain score reductions were double in the open  “powerful painkiller” group compared to the hidden ones.

Finally, three further topics for the “continuous improvement” theme, all of which i will talk about more in the future.

The first is transthoracic echo for use by anaesthetists in preoperative assessment. This is something that was big when I was doing my fellowship at the Royal Melbourne Hospital and is spreading around the world rapidly. In this month’s Anaesthesia the RMH team have provided the first (weak) evidence that preoperative echo may improve outcome, instead of simply changing management (which has been shown in previous studies). The study is observational, of poor quality, subject to the Hawthorne effect and shows an implausibly large mortality difference, but for all that makes pleasing reading for transthoracic echo exponents such as myself (reference here).

The second is the use of dexamethasone to prolong peripheral nerve blocks. This is something we have been doing recently in our hospital in Mackay in Australia, and the results can only be described as “spectacular, bordering on scary” – 24-30 hours duration from a single shot interscalene block, including complete motor block at 24 hours. This is consistent with studies showing dexamethasone effectively doubles the duration of most nerve blocks. Just remember that the phrenic nerve is also paralysed for 24 hours!

When I first read about this I had some concerns on potential neurotoxicity, but these were alleviated by 2 things.  The first of these were the words of a chronic pain physician colleague who stated that they add dexamethasone to every block they do, have been doing so for years and have had no problems. The second is a study showing that in an animal model dexamethasone was significantly less neurotoxic that ropivicaine, and the ropi/dex combination was less toxic than other common combinations such as ropi / buprenorphine and ropi/ clonidine (reference here and here and here)

The final interesting note is on SCDs- the sequential calf and thigh compressors now ubiquitous on the legs of patients having surgery in our hospitals. Two recent articles showed that they reduce intraoperative hypotension- a bonus that at first seems unexpected until you think about it, then seems quite logical.

Reduced hypotension for caesarian:  here

This study used a variation of the normal compressors with higher pressures and longer compression times: here

EUSOS follow up – is it the beds?

Over the next few months I am sure that the real reasons for the comparatively poor outcomes of Irish patients in the EUSOS study will emerge. In the meantime, we can only guess the reasons. Aside from blaming surgeons for poor patient selection (which is suspiciously convenient), case volume may be a problem, the time of day (exhaustion), the amount of emergency surgery (including case volume) or the issue may lie in our own backyard – in the availability of beds for high risk postoperative patients. Emergency surgery patients, in particular, do poorly.

A US study of 25,710 nonemergency colorectal resections performed at 142 hospitals reported a 1.9% (492 patients) mortality rate. For emergency colorectal resection the mortality rate was 15.3% (780 of 5,083 patients). Fifty percent of emergency surgery patients had at least 1 complication versus 24% of elective surgery patients. This is horrifying.

The first report of the UK emergency laparotomy network (here), published in the BJA, presents similar mortality data. As a guide, mortality rates for major elective general surgery have been reported as follows: colorectal resection – 2.7%,  oesophagectomy – 3.1%, gastrectomy – 4.2% and liver metastasis resection – 1%. In this study (data from 1853 patients were collected from 35 NHS hospitals) the unadjusted 30 day mortality was 14.9% for all patients and 24.4% in patients aged 80 or over.

We are aware that emergency surgery patients come in at all hours of the night and are frequently operated on by junior doctors. The time of day was an issue (table below) – 30 day mortality was 50% higher if surgery took place between midnight and 8am. Obviously confounders may be present – surgeons may only take the sickest patients to theatre at night, and this may represent selection bias.

Time of day* n Consultant anaesthetist present (%) Consultant surgeon present (%) 30 day mortality (%)
08:00–17:59 1044 75.2 80.8 14.2
18:00–23:59 442 54.8 67.7 17.8
00:00–07:59 152 40.8 61.8 20.3

Bad outcomes occurred for patients admitted under a medical service who actually had a surgical problem, increasing age, increasing ASA physical status.

What about beds? “Of the patients who were felt to need intensive care immediately after surgery, 99% were transferred to a level 3 bed. Similarly, 89% of those who were judged to require a high-dependency bed received this level of care, with a further 4% receiving level 2 care in an ICU bed. Mortality in patients returning to the ward (level 1) was 6.7%, HDU 10.1%, and ICU 30.7%. 2.2% of patients were cared for after operation in an extended recovery area (presumably because there was no HDU bed available), and this group had a mortality of 13.5%. For the group of patients aged 60 or greater, and of ASA III or more (∼50% of all patients), 22% returned to the general ward after operation and had a mortality of 17.8%.” One must presume that this 22% represented at least part of the 11% that didn’t get the needed HDU beds. Hence, one could crudely argue that the patients that needed HDU beds but didn’t get them had an absolute mortality risk increase of 7.7% (the authors do not give us sufficient data to make direct comparisons, but more than 50% of patients were >60y and ASA III or greater). The overall mortality for patients sent to a regular ward was 6.7%, which appears to be very high when compared with data from general elective surgery (above). However, a recent study of all 160,920 patients who underwent bowel resection for colorectal cancer between 1998 and 2006 in the English NHS reported a mortality rate of 6.7%

These data at least suggest that lack of availability of a HDU/ICU bed significantly increases the risk of poor postoperative outcomes for emergency surgical patients.

The utilization of critical care services has been known to be suboptimal for many years. A previous study, published in Anaesthesia (here) looked at 26000 patients undergoing surgery in an NHS trust: “only 852 (35.3%) high-risk patients were admitted to a critical care unit at any stage after surgery. Of 294 high-risk patients who died, only 144 (49.0%) were admitted to a critical care unit at any time and only 75 (25.6%) of these deaths occurred within a critical care area. Mortality rates were high amongst patients discharged and readmitted to critical care (37.7%) and amongst those admitted to critical care following initial postoperative care on a standard ward (29.9%).” So, inadequate numbers of ICU/HDU beds are associated with poor outcomes, and early discharge (presumably for bed pressure) and readmission is associated with 1/3 of patients dying.

Ireland has a similar number of critical care beds per 100,000 population (6.5/100,000) to the UK (6.6/100,000). In a recent pan European study conducted by Andy Rhodes (here), Ireland ranked 26th out of 31 (UK was 25th) in critical care bed numbers per 100,000. The European average was 11.5. Overall, Ireland ranked 28th/31 for number of acute care beds and  23rd out of 31 for ICU beds as a % of acute care beds. So, we have very few beds for sick patients, and of these very few of them are critical care beds. Ireland spends 7.2% of GDP on healthcare (15th/31) and has the 6th highest GDP in proportion to ICU beds. In other words – we spend very little money comparatively on critical care compared with Europe. This might reflect the fact that we have the 2nd youngest population in Europe (10.4% are 65 or older).

In summary – is lack of critical care beds a likely factor for Irelands poor showing in EUSOS: almost certainly. Do these studies fully explain the difference – no! Unfortunately, the OR death was still 2.6 times the UK with a similar number of ICU/HDU beds. It could be argued that the bed numbers are inflated in Ireland, due to poor distribution between hospitals – community hospitals have underused ICU beds, referral centers have inadequate capacity. But that is another discussion….

At last – Chloride is nephrotoxic

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!

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!

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.