Author Archives: Pat Neligan

About Pat Neligan

Pat Neligan lives and works in Galway, Ireland

Troponin Leak Postop – what does it mean?

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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?

The Obesity Paradox – Weight there’s more!

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chandler-weightThe media are constantly harping on about the obesity epidemic – “two in three of us are fat – this is going to lead to an explosion of obesity related morbidity – heart disease, cancer, cerebrovascular disease, crumbling joints etc.” It never seems to occur to the same talking heads on television and in print media that life expectancy continues to improve worldwide, without any great new medical advances over the past 2 decades (during which the obesity epidemic emerged). In perioperative medicine and critical care we have data that an “obesity paradox” exists – that individuals with a BMI between 25 and 35 (overweight and grade 1 obesity) have lower mortality rates in perioperative medicine (references 1. Here, 2. Here) and critical illness (references 1. Here; 2 Here; 3 Here; 4. Here). The reasoning why overweight and mild obesity (being chubby) may confer benefit is an increase in physiology reserve, delivered in part by an increase in lean body mass. As patients become heavier (body mass index; BMI>35, grade 2 and 3 obesity), they start manifesting mass related injury and metabolic disease. Metabolic syndrome unquestionably increases long term risk (here).
But what of the general population? Life insurance companies continue to penalize chubby folks based on actuarial figures from the 1960s – it that fair? It turns out that it is not. Hold your breath – a 2.88 million patient meta analysis performed by a group of US researchers and published in last week’s JAMA (here), has completely moved the goalposts for desirable BMI. In terms of Hazard Ratio (where HR of 1 = BMI 20-25), BMI of 25-30 had a HR for all cause mortality of 0.94 (lower; CI 0.91-0.96). BMI  30-35 had HR 0.95 (lower; but CI 0.88 – 1.01 NS). BMI 35-40 HR 1.29 (higher CI 1.18-1.41). In other words – overweight patients had LOWER all cause community mortality than BMI 20-25. Being obese up to BMI 25 did NOT increase mortality risk, and only individuals with BMI >35 had increased risk.

People – you need to face up to it: OVERWEIGHT IS THE NEW “NORMAL.” Perhaps “Chubby Chandler (above)” was the healthy one.

More comments to follow.

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

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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.

Withold ACE inhibitors for surgery? Think Again

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Anecdotally, the majority of anesthetists withhold ACE inhibitors (angiotensin converting enzyme inhibitors ACEI)  on the day of surgery because of concerns regarding hypotension, particularly in operations that may involve sympathectomy (spinal anesthesia) or blood loss. This appears to be a particular problem with angiotensin receptor blockers (here). We already know that withholding beta blockers and statins preoperatively is associated with an increase in the risk of myocardial ischaemia (reviewed here). ACEI were the wonder drugs of the 1980s: 1. use of ACE inhibitors provide long-term cardiovascular protection and reduce ischemic events and complications; 2. early ACE inhibitor therapy has been demonstrated to produce improved survival and heart function benefits in patients with acute myocardial infarction; 3. they are remarkably effective drugs in the treatment of heart failure and hypertension; 4.  ACEI delays the progression of diabetic nephropathy. So, is it wise to withhold these drugs in the preoperative period?

The following is a quote from a review on this topic in the Postgraduate Medical Journal: “The use of these agents before surgery has been associated with a variable incidence of hypotension during the initial 30 min after induction of anaesthesia; however, these hypotensive episodes have not been conclusively linked to any significant postoperative complications…” (here).

The following is a quote from an excellent review of the topic of drug withholding in preoperative patients: ACEI “intensify the hypotensive effects of anesthesia induction. Because angiotensin II plays a key role in maintaining circulating volume in response to stressors, volume deficits can occur in ACE inhibitor-treated patients as angiotensin II cannot compensate for venous pooling of blood, resulting in diminished cardiac output and arterial hypotension. However, continued renin-angiotensin system suppression may protect regional circulation, as has been demonstrated by reduced release of cardiac enzymes with ACE inhibitor continuation (compared with interruption) in cardiac surgery patients. ACE inhibitors also have a renal protective effect, preserving glomerular filtration rate in patients undergoing aortic abdominal aneurysm repair or coronary artery bypass graft surgery. Hypotension with ACE inhibition is treatable with sympathomimetics, alpha-agonists, and intravenous fluids.” (here). Essentially the author is referring to phenylephrine and vasopressin.

So, it may surprise you to discover that there are emerging data to support the continuation of ACEI in the preoperative setting, particularly in cardiac surgery patients. A recent article in circulation (here – subscription required – the HSE has a 1 year embargo – cheapskates!) suggests that withholding ACEI after cardiac surgery is associated with increased incidence of non fatal cardiac events:

This was a “prospective observational study of 4224 patients undergoing coronary artery bypass graft surgery (CABG). The cohort included 1838 patients receiving ACEI therapy before surgery and 2386 (56.5%) without ACEI exposure. Postoperatively, the pattern of ACEI use yielded 4 groups: continuation, 915 (21.7%); withdrawal, 923 (21.8%); addition, 343 (8.1%); and no ACEI, 2043 (48.4%). Continuous treatment with ACEI versus no ACEI was associated with substantive reductions of risk of nonfatal events (adjusted odds ratio for the composite outcome, 0.69; 95% confidence interval, 0.52–0.91;P=0.009) and a cardiovascular event (odds ratio, 0.64; 95% confidence interval, 0.46–0.88; P=0.006). Addition of ACEI de novo postoperatively compared with no ACEI therapy was also associated with a significant reduction of risk of composite outcome (odds ratio, 0.56; 95% confidence interval, 0.38–0.84; P=0.004) and a cardiovascular event (odds ratio, 0.63; 95% confidence interval, 0.40–0.97;P=0.04). On the other hand, continuous treatment of ACEI versus withdrawal of ACEI was associated with decreased risk of the composite outcome (odds ratio, 0.50; 95% confidence interval, 0.38–0.66; P<0.001), as well as a decrease in cardiac and renal events (P<0.001 and P=0.005, respectively).”

There are some unpublished data that continuing ACCEI up to surgery (and presumably afterwards) is associated with lower 30 day mortality (here). Preoperative use appears to be associated with fewer major adverse events after cardiac surgery (here), and even when no benefit has been demonstrated the agents appear to be safe (here).

So, think twice before you stop the ACEI in your preoperative visit. Nevertheless, I am still going to avoid these agents when anesthetizing patients in the beach chair position (here).

EUSOS follow up – is it the beds?

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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….

24 hour Intensivist Presence – desirable? Maybe. Efficient, Economic and Effective – Unlikely

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Few issues have been more controversial in the past 20 years than the implementation of the intensivist model. Fundamentally this involves delegation of primary responsibility for critically ill patients to a narrow group of clinicians, whose primary training may be in an entirely different specialty. Hence, surgical patients may be managed by internists, and medical patients may be managed by anesthetists. I like to think of intensivists as coordinators of patient care, experts at resuscitation, who pay meticulous attention to detail and careful users of resources. As a result, each organ system does not have it’s own consultant, and medicines, interventions and tests are reduced, saving the institution a lot of money and resources.

Whether or not intensivists improve patient outcomes, versus primary medical or surgical teams rounding on patients, remains controversial. I have written about this in detail elsewhere (here subscription needed).  To summarize: daily rounds by an intensive care specialist improve outcomes in high risk surgical patients; intensive care teams (multidisciplinary) improve outcomes, as does the presence of a ICU medical director who sets standards. An article in Annals of Internal Medicine (conducted by well known intensivists) found that, in a study of >100,000 patients, critically ill patients managed by intensivists had worse outcomes (here). Patients managed by critical care physicians were sicker, had more procedures, and had higher hospital mortality rates than those managed by other physicians. I have always found this article confusing – for example in the non-intensivist model there were hospitals that had critical care fellows but no intensivist! The assumption that leads to the headline (“intensivists kill patients”), is that SAPS II is a good predictor of mortality and that adjustments based on SAPS II can separate out patients. If SAPS is not so good, then adjustments for severity of illness are meaningless. Also, there were significantly more patients transferred from other hospitals and more patients ventilated on admission in the CCM (intensivist) model. This suggests lead time bias: patients with similar severity of illness scores on admission to ICU that have been pre-resuscitated or transferred have worse outcomes.

The Irish government clearly believe in the intensivist model, as they seem to think that having us present in the ICU 24/7 will improve outcomes and save lots of money. In today’s Irish Times:

“For the first time, consultants in areas such as emergency medicine, intensive care, neonatology and obstetrics will be rostered on a 24-hour basis, working eight-hour shifts. Dr Reilly has said the proposals could save up €200 million.” (article here). I don’t know how the geniuses in the Department of Health have come up with this number, but it is complete fiction. In addition, for a Hospital to provide 24 hour consultant in house cover for ICU, I calculate that this would require approx €1 million a year in direct salary costs (5 FTEs to cover around the clock plus 2 or 3 more to cover their daytime assignments – remember the EWTD applies to consultants as well). This may appear insignificant compared with the staggering savings that they are anticipating – but there is no systematic proof that over investigation (where available and it is not) at night, and over treatment (with what?) at night and bad decision making, by registrars, is costing the health system a fortune. In fact – there is not a single study published anywhere ever that shows that having a consultant intensivist present for patient resuscitation improves outcomes. Outcome improvement has been demonstrated in scenarios where patients have received timely fluids and antibiotics, and subsequent care with ventilator strategy, sedation and mobilization. Has anyone ever studied the 24 hour intensivist model? Yes they have….

A study in the Lancet in 2000 suggested that 24 hour availability of intensivists (the current model in ALL Irish level 3 ICUS) significantly improved outcomes (here). A group from Saudi Arabia claimed the 24/7 staffing led to similar mortality out of hours as within weekday hours (here) proving – well nothing. A nice pro-con debate on this topic can be read in Critical Care (here). A passionate plea for 24/7 coverage can be read in the “blue journal” (here). A core discussion point is that patients that are admitted out of hours (9-5 Monday to Friday) appear more likely to die. This assumes that worse outcomes are due to lack of consultant staffing in the ICU rather than confounders like: patient was getting sick, but no GP available, no elective surgery admitted out of hours, fewer investigations (radiology) available out of hours, patients on wards not being seen by primary care team out of hours etc. In other words, it may be the health system rather than the absence of continuous critical care consultant staffing that is at fault. A study from Paris suggested that out of hours admission patients did better! (here). A US study suggested no difference (here). Indeed, even in July changeover season, mortality is not greater (here). Moreover, papers that claim cost savings tend to massage their data (here).

In the NEJM in May 2012, a group from Pittsburgh looked at night time physician (intensivist) staffing in ICU versus outcomes in North America (article here). What the study showed, in a nutshell, was if the hospital had an intensivist and a critical care team during the day, having a consultant present, on site, at night made no difference to outcomes (our current model in Ireland). However, in hospitals where there was no critical care team during the day (low intensity staffing), having an intenisivist at night improved outcomes [I am still trying to figure out what kind of ICU would pay a consultant at night but not during the day – perhaps they were covered by Tele-ICU]. Also, having any doctor dedicated to the ICU at night (a resident) improved outcomes – very much our model in Ireland.

So, before we are forced to embrace 24/7 cover perhaps it is worth questioning why and for what benefit. I am not suggesting that there should not be 24/7 anesthesia, EM  or obstetrics (where you would anticipate fewer lawsuits, I presume) coverage, I am just relaying the best current evidence, which is that expending 5 FTEs worth of staff to cover 24/7 in adult ICU is not supported by best available evidence.

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.

The sweet smell of obesity

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You may recall a movie from a few years ago called “Super Size Me” that featured Morgan Spurlock eating nothing but McDonalds food for a month. If offered a super sized meal, he said – yes. He became lethargic, gained weight and developed a fatty liver. The message was that if you ate highly calorific fatty food, you would become seriously unhealthy. I have argued, for some time, that Morgan should go back to McDonalds for a month and eat the same food, but drink diet sodas. There is an abundance of data that the high fructose corn syrup (HFCS) in US drinks defeats the normal satiety pathways, increases appetite and leads to visceral obesity and metabolic disease (don’t believe me? Click here). Sugar sweetened drinks are likely nearly as bad. I have never understood why anyone overweight would voluntarily drink sugar sweetened drinks when they can get essentially the same product calorie free (“diet” drinks). I remember American colleagues justifying this with comments like “I don’t trust aspartame” (it has been used for 40 years no evidence it causes harm to humans – click here) – the reply <but you trust HFCS! A Frankenfood>.
Last week Philip Boucher Hayes presented an RTE documentary on Ireland’s dietary habits. The programme painted a nice picture of how today’s obesity epidemic is turning into tomorrow’s cancer horror story. It turns out that Irish people are among the biggest sugar consumers in Europe; we are particularly fond of chocolate: we are a nation of carb addicts. Carb addiction shares many of the traits of opioid addiction.
So those of us who have long argued that the obesity epidemic is a problem of excess carbohydrates rather than excess fat will take note of no fewer than 3 papers in this weeks New England Journal. The most interesting of the papers, which came from Holland, randomized children aged 5 to 12 to 8oz (236ml) of sugar sweetened drinks per day (link here) (we don’t know exactly what product but it was not a common brand in Ireland (company) let’s call it “sugar drink”) versus blinded administration of 8oz of calorie free drink per day (“diet drink”). Thats it. They started with 641 normal weight children. 18 months later the children given the sugar drink had gained, on average, 1kg more in weight (2.2 pounds) compared with the other group. Children in the sugar drink group were pudgier (skinfold-thickness measurements, waist-to-height ratio, and fat mass).
So, sugar-drinks make you fat, and diet-drinks probably don’t. But what if we have been drinking sodas for years, are overweight and decide to quit? A second study, of adolescents, conducted in the USA (click here), randomized 224 adolescents (overweight/obese) to a programme (1 year) that involved giving up sweetened-sodas (HFCS). At 1 year there was a 2kg difference in weight and a significant difference in BMI between the 2 groups. This had disappeared at 2 years. In other words, presumably, they started drinking sodas again.
What about that skinny guy that you know who drinks 5 cans of Coke a day. It turns out that if you are genetically predisposed to becoming obese (your parents are overweight) then you are more likely to suffer the adipogenic effects of sweetened sodas (click here). In other words, if you have a belly, don’t give your kids sugar cola  – ever. Don’t start them drinking sodas. Don’t buy sodas.
So here is the issue – they have banned smoking just about everywhere (including potentially in your own car if your children are present), based on very questionable evidence that secondary inhalation of (“passive”) smoke injures you. These data represent clear evidence of the dangers associated with a series of food products with no nutritional value that have a ready made replacement (diet soda) made by the same manufacturers. Shouldn’t we be banning the sale and administration of sugar-sodas to children (I was horrified to hear in the RTE documentary that babies at 6 months were being give carbonated drinks)? Read here to enjoy a wonderful discussion of this topic.
Now if they could only come up with diet pizza, diet chips and diet scones……