ICU Rounds Report - November 24th, 2010

Metformin Acidosis - The ICU Yeti? You've probably heard someone call oxygen toxicity the sasquatch of the ICU - frequently talked about but never seen. Speaking of mythical creatures - how many of you have actually seen acidosis from metformin? In 1950, metformin's cousin phenformin was introduced and was widely used as an oral hypoglycemic. Twenty-five years and over 300 cases of frequently-fatal metabolic acidosis later, the FDA removed the drug. When metformin (Glucophage), a chemically similar biguanide drug, was introduced in in 1995 there was wide spread concern about metabolic acidosis. Merck, the maker, and the government sponsored multiple large trials which, in aggregate, evaluated over 36,000 patient-years without a single incidence of acidosis due to metformin.

By contrast, some case reports have shown up from time to time. The FDA reports that among the first one million treated with metformin, 47 cases (20 fatal) were reported. Forty three of these occurred in the setting of acute renal failure and the rest occurred during sepsis, overdose or heart failure. In other words, when used according to the label, there is zero chance (or close enough to zero as to be clinically irrelevant) of the drug causing acidosis.
Salpeter S, Greyber E, Pasternak G, Salpeter E: Risk of fatal and non-fatal lactic acidosis with metformin in type 2 diabetes. Cochrane Database Syst Rev 2:CD002967, 2003
Stades AME, Heikens JT, Erkelens DW, Holleman F, Hoekstra JBL: Metformin and lactic acidosis: cause or coincidence? A review of case reports. J Int Med 255:179–187, 2004

Neurogenic Pulmonary Edema.  After major head injury (status, trauma, hemorrhage) the aveloli and interstitial spaces in the lungs will occasionally fill with fluid causing patients to cough blood, breath quickly and desaturate. On autopsy studies, up to half of patients with those diseases will have evidence of it. We're not quite sure how it happens, but based on animal studies it is likely related to large, sudden increases in sympathetic outflow which causes 1)pulmonary microvascular damage 2)intense pulmonary vasocontriction raising transcapillary pressures and/or 3) acute, transient RV/LV dysfunction. The effect can be blocked with phentolamine in animal models. No human trials have been done to see if alpha blockade is safe or reasonable.

Onset is typically quite rapid after the head insult. Diagnosis is one of exclusion. Treatment is supportive and should be directed at the cause and sequelea of the head injury. Like neurogenic heart dysfunction, the huge majority of cases are transient and improve with time making prognosis more dependent on the extent of the head injury. This disease is sometimes confused with ARDS and may look radiographically similar. The treatment and prognosis are very different, however. Unlike ARDS, high PEEP levels and permissive hypercapnia should be avoided because of their effect on ICP.
Baumann, A, Audibert, G, McDonnell, J, Mertes, PM. Neurogenic pulmonary edema. Acta Anaesthesiol Scand 2007; 51:447.

ICU Rounds Report - November 19th, 2010

From Lis
How bad is my hemorrhage, Doctor? Drs. Hunt, Hess and Fisher are often employed to help. Since the 1930's physicians have attempted to compile an adequate grading scale for sub-arachnoid hemorrhage. Ideally this scale would guide management decisions affected by severity, provide a working prognosis, allow for treatment research among the various grades, and monitor changes in severity in an individual patient.

Hunt and Hess (used at UVa):
The Hunt and Hess scale is a 1968 modification of an older scale (Botterell, 1956). The scale was designed to assess surgical risk and if patient is a surgical candidate when is the ideal time to operate. Today it is used to evaluate clinical outcome, which according to one study Hunt and Hess was the strongest predictor of clinical outcome at 6 months when compared to GCS/WFNS (Aulmann, 1998). The scale is built on three axes:
a. Intensity of meningeal inflammation reaction
b. Severity of neurological deficit
c. Level of arousal
d. Presence of significant associated systemic disease à increases grade by one level

The benefit of Hunt and Hess lie in its easy administration. Disadvantages include the low inter-rater reliability (κ = 0.42), vague terminology, and requiring the clinician to evaluate all three axes on a single scale. This forces us to choose which axis is most important and contributes to lax category boundaries and relatively arbitrary grading assignments. Finally, data indicates that there are only differences in outcome associated with some of the grades - specifically Grade 2 and 3 and Grade 3 and 4.

1  Asymptomatic or mild headache and slight nuchal rigidity
2  Moderate to severe headache, nuchal rigidity, no neurologic deficit except cranial nerve palsy
3  Drowsy or confused, mild focal neurological deficit
4  Stuporous, moderate or severe hemiparesis, possible early decerebrate rigidity and vegetative  disturbances
5  Coma, decerebrate rigidity, moribund appearance

Fisher:
The Fisher Scale is a 1980 scale designed to predict cerebral vasospasm based on the blood pattern seen on the first post bleed CT scan. The main advantage of the Fisher scale is the high level of inter- rater reliability (κ = 0.90). Since its development, clinicians have started using it as a clinical outcome predictor as well. However the newer scales are combining patient age, Hunt and Hess, and Fisher in order to improve the predictive strength of the scale. One example is the Olgilvy and Carter scale.

1 No blood detected
2 Diffuse deposition or thin layer with all vertical layers (in interhemispheric fissure, insular
cistern, ambient cistern) less than 1 mm thick.
3 Localized clot and/or vertical layers 1 mm or more in thickness
4 Intracerebral or intraventricular clot with diffuse or no subarachnoid blood
Aulmann C, Steudl WI, Feldmann U. [Validation of the prognostic accuracy of neurosurgical admission scales after rupture of
cerebral aneurysms]. Zentralbl Neurochir 1998;59:171–180.
Hunt W, Hess R. Surgical risk as related to time of intervention in the repair of intracranial aneurysms. J Neurosurg 1968;
28:14.
Rosen DS, Macdonald RL. Subarachnoid hemorrhage grading scales: a systematic review. Neurocrit Care. 2005;2(2):110-8.
Review.

STATs note: Kappa scores are generally thought to be a more robust measure than simple percent agreement calculation since κ takes into account that the agreement may be occurring by chance. Recall that if the raters are in complete agreement then κ = 1. If there is no agreement among the raters (other than what would be expected by chance) then κ ≤ 0.

κ	Interpretation
< 0	No agreement
0.0 — 0.20	Slight agreement
0.21 — 0.40	Fair agreement
0.41 — 0.60	Moderate agreement
0.61 — 0.80	Substantial agreement
0.81 — 1.00	Almost perfect agreement

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ICU Rounds Report - November 18th 2010

Sticky Platelets. Back in the days when the only thing to do with an MI was to talk about it (i.e. the 60 and 70's), physicians noticed that heart attacks tended to happen most commonly in the morning. Same for strokes and TIAs. Why? Partly because platelets tend to have diurnal variation and aggregate more avidly in the AM, particularly when people first assume the upright position after lying recumbent all night. These events also to the corresponds to the typically highest blood pressures of the day.

The platelet part of this theory was confirmed in the 1980's in a series of studies that measured platelet function in healthy men around the clock. Reliably, platelets are more likely to aggregate between 6-10am. The implications of this are two: first, don't get out of bed unless you really have to. Second, if you're treating patients at risk for arterial thrombosis with anti-platelet agents, make sure you're covering the morning.
Tofler GH, Concurrent morning increase in platelet aggregability and the risk of myocardial infarction and sudden cardiac death. N Engl J Med. 1987 Jun 11;316(24):1514-8.

Teachable Moments. Patients undergoing major surgery or trauma are significantly more likely to pay attention to healthful suggestions, like to drink less or stop smoking. Multiple randomized trials of smoking cessation prior to major surgery have shown big benefits, particularly with cardiac and wound complications. Other trials have shown that repeatedly reminding patients to stop smoking and drink less makes an real, measurable impact. This is especially true at stressful times (i.e. new cancer diagnosis, major surgery, trauma).

Alcohol abuse is common problem in our patients and of course a significant risk factor for trauma. Up to 50% of trauma patients will screen positive to alcohol abuse. To decrease the trauma burden, researcher at Harborview Medical Center randomized over 700 trauma patients who screened positive for abuse symptoms to a brief (30 minute) intervention from an addiction counselor or routine care. Patients were told they were in a study regarding trauma outcomes and were not aware that the addiction intervention was part of the study.  The results were striking.

At one year, alcohol use was reduced (self-reported) by 22 drinks per week (P<0.03). There was a 47% reduction in injuries requiring either emergency department or trauma center admission (hazard ratio 0.53, 95% confidence interval 0.26 to 1.07, p = 0.07) and a 48% reduction in injuries requiring hospital admission (3 years follow-up).

Given the risks, benefits and costs of this intervention, it seems like alcohol counseling should be routinely given to at risk trauma patients. While that happens from an institutional stand point, it seems reasonable for all of us to take some time and address alcohol and smoking in our patients in these "teachable moments."
Warner, DO. Surgery as a Teachable Moment Lost Opportunities to Improve Public Health Arch Surg. 2009;144(12):1106-1107.
Shi, Y et Al. Surgery as a Teachable Moment for Smoking Cessation. Anesthesiology.  2010 112(1): 102-107

ICU Rounds Report - November 17th 2010

The TRACS trial is here! More than 10 years after the publication of the TRICC trial, we're finally getting some more proper, randomized data about blood transfusion in critical care. JAMA last month published the long awaited results of a single center RCT in Brazil involving over 500 patients randomized to liberal (transfuse to >30% hematocrit) vs conservative (>24%) transfusion strategy in patients undergoing routine CABG and/or valve surgery requiring bypass. The intervention significantly reduced PRBCs transfusion (78% and 47% receiving, respectively). Morbidity and mortality was the same in both groups.

Unlike our practice at UVa, all the blood given was young (median age 3 days) and not leukodepleted. Older blood, as is frequently transfused here, has been associated with worse outcome while leukodepletion (standard here) appears to improve outcomes.

In the same issue of JAMA, researches using the STS database found transfusion practices among 700 US hospitals for 100,000 patients undergoing CBP showed wide variance in the rates of product transfusion (RBC (7.8%-92.8%), plasma (0%-97.5%), and platelet (0.4%-90.4%)). These differences persisted after adjusting for hospital and patients factors. Like the TRACS trial, there was no apparent difference in mortality or morbidity.

Taken together, these results point to a continued epidemic of costly, unnecessary and potentially dangerous over-utilization of blood products. Previously, this was, in part, due to a lack of RCT-based evidence in this patient group. Now, this is no longer true. We can say with assurance that transfusion of even a single PRBC unit has real risks that must be carefully balanced against benefits which, while real, are increasingly harder to find.
Hajjar LA, Vincent J-L, Galas FRBG; et al. Transfusion requirements after cardiac surgery: the TRACS randomized controlled trial. JAMA. 2010;304(14):1559-1567
Bennett-Guerrero E, Zhao Y, O'Brien SM; et al. Variation in use of blood transfusion in coronary artery bypass graft surgery. JAMA. 2010;304(14):1568-1575.

A FAST HUG Every 5.7 weeks on rounds, someone mentions the mnemonic developed by critical care god Jean Louis Vincent, FAST HUGS. Here it is written down so you have a nice reference to check in case you fancy yet forget it. You can add (although Jean Louis doesn't think you should) a BID, to emphasize this should be done at least twice a day.

F Feeding
A Analgesia
S Sedation
T Thromboembolic prophylaxis

H Head of bed elevation
U Ulcer (stress) prophylaxis
G Glycemic control
S Spontaneous breathing trial

B Bowel regimen
I Indwelling catheter removal
D De-escalation of antibiotics
Vincent JL: Give your patient a FAST HUG (at least) once a day. Crit Care Med 2005; 33:1225–1229

ICU Rounds Report - Nov 12th 2010

We're back! I've been in the TCV-PO, where there was neither time nor medical students to help with the report. Now, the 'break' is over. Thanks for reading!

Colchicine is commonly used for both acute treatment and the prevention of gouty arthiritis. We've recently had a patient inadvertently continued on their home dose, which is problematic for many reasons.  But first some background, and an interesting aside about American drug policy. The FDA has made arrangements for companies to test drugs grandfathered into common usage prior to the approval process in exchange for a few years of market exclusivity. Ostensibly, this is because the FDA cannot afford to run the trials themselves. Colchicine, despite being used for centuries, was recently approved (2009) after a drug company paid for a large clinical trial that proved efficacy according to modern FDA standards. Accordingly, exclusive approval to market the drug was given to URL Pharma and they promptly raised the price per tablet from $0.08 to $4.85, a move expected to cost Medicare over $50,000,000 this year alone. So, where's the savings?

But I digress. How does it work? The drug has several effects, including decreasing urate cyrstal deposition, its primary therapuetic effect. Unfortunately, it also has potent anti-mitotic effects, poisoning the mitotic spindle in a dose-related manner. It's side effects are related mostly to this and are seen in sites with rapidly dividing cells: anemia, neutropenia, GI mucosal sloughing leading to upset, gastritis, etc. More severe overdosing looks like arsenic poisoning and causes renal failure, pulmonary hemorrhage, shock and death. Needless to say, the drug should routinely be held in critically ill patients. For the rare ICU patient dealing with acute gout, corticosteroids remain a much better choice.
Kesselheim AS, Solomon DH (June 2010). "Incentives for drug development--the curious case of colchicine". N. Engl. J. Med. 362 (22): 2045–7.

The Perfect PEEP? The ARDS net trial seems to have helped settle the question of what tidal volumes we should be using, but finding the best PEEP level has been a harder question to settle. Based on the ARDSnet recommendations, our current practice (basically whatever amount above 5 cm H2O that is needed to oxygenate) does not take into account individual characteristics such as chest wall and lung compliance that might have an impact. Three large trials comparing high to low PEEP (ALVEOLI, LOVS and EXPRESS studies) have been done and each showed some improvement in oxygenation with more PEEP, but have not shown a mortality benefit.

Now, a group at Harvard has published the results of a small, single ICU pilot trial using intraesophageal ballons measuring (hopefully!) transpulmonary pressure, allowing PEEP to be adjusted based on individual respiratory compliance curves. The results of the pilot are positive and show improvement in recruitment, compliance and oxygenation. Whether this will result in a clinically meaningful benefit can only be shown with a much bigger trial, but the idea is exciting. Maybe Stuart could combine this with a NAVA catheter and we'll have found the perfect ventilator strategy?
Talmor D, Sarge T, Malhotra A, O'Donnell CR, Ritz R, Lisbon A, Novack V, Loring SH: Mechanical ventilation guided by esophageal pressure in acute lung injury. N Engl J Med 2008, 359:2095-2104

Beta Blockers for Respiratory Failure. A soon-to-be published paper in Critical Care Medicine reminds us once again that patients admitted on beta-blockers do much, much better when they are continued. This paper, using data from the BASEL II ICU trial, evaluates patients admitted to an ICU with respiratory failure, of any cause. In this mixed group of non-septic patients admitted with respiratory failure (pneumonia, heart failure, asthma, COPD and pulmonary embolism) those on beta-blockers at the time of admission had much lower 28 day and one year mortality (OR 0.32 [0.18 – 0.52] P<0.0001), regardless of the eitology of the respiratory failure.  Further, discontinuing beta-blockers at admission was found to be quite hazardous in this group (one year mortality 82 vs 41%, P <0.000001). Patients who were not on beta-blockers at the time of admission but placed on them prior to discharge had their mortality rate reduced by a third (p<0.001).

These results are a retrospective look at prospective data from a trial evaluating something else (B-type natriuretic peptide -guided management strategy on short-term outcome). Causality isn't proven with these results and they don't therefore justify placing patients admitted with respiratory failure on beta-blockers. They do, however, add a another shovel to the growing mountain of evidence that patients on beta-blockers at the time of admission should, whenever possible, have the beta-blockers continued. They also raise the question of whether beta-blockers should be used routinely for respiratory failure. Prior to this paper, that suggestion seemed crazy (metoprolol for asthma? carvedilol for acute PE?!)That question needs further study.
Noveanu M, et al. Effect of oral beta-blocker on short and long-term mortality in patients with acute respiratory failure: results from the BASEL-II-ICU Study Critical Care 2010, [in press] 14:R198 doi:10.1186/cc9317
Noveanu M, et al. Use of B-Type Natriuretic Peptide in the Management of Hypoxemic Respiratory Failure. Eur J Heart Fail 2010:[in press].

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