As usual, the 4th Annual Critical Care Symposium put on by Veerappan in Manchester, UK was superb. There were around 200 attendees this year, and my biggest concern is that the meeting will “catch on” and get too big. The faculty which Veerappan manages to assemble for these meetings is astonishing, and a wide range of clinical and basic science topics are always discussed. Unarguably, at least to me, the most valuable aspect of this meeting is that it really doesn’t matter if the specific topic or development you are interested in is on the program or not, because it is nearly certain that among the faculty or attendees there will be someone there who knows what you want to know – and, just as importantly, will have both the time and the inclination to talk to you at length about it. With likes of Bleck, Fink, and Singer to chat with, anything I wanted to know about current developments in the pathophysiology and experimental treatment of sepsis, ischemia and shock is only a question or two away from being answered.
Professor Sheldon Magder gave an excellent presentation on the Stewart Approach to acid & base management and presented the strong ion dissociation (SID) approach in a concise and lucid manner. Sheldon’s slides are a treasure since they provide the teaching tools necessary to make SID comprehensible and clinically applicable. I had previously asked if anyone on CCM-L had any slides on SID and (apparently) no one did, aside from Farhad, who had one. Thanks to Sheldon, and the Manchester meeting, I now have a great set of slides – including some case presentations illustrating the importance of SID which Sheldon did not have time to present.
Dr. Roop Kishen gave a good overview of RRT and lead off a “mini-block” of related topics including a presentation on drug dynamics in RRT by Professor Jeff Lipman and a review of anticoagulation in RRT by Dr. Claudia Teles. It goes without saying that Claudia, being a hematologist obsessed with clotting, platelet activity, and all things affecting formed elements of the blood provided insight into the effects of various anticoagulation modalities in RRT on the immune inflammatory response and blood cell integrity in response to extracorporeal manipulation in the presence of different anticoagulants.
Kishen addressed the controversy over which RRT modality to use, and noted that currently the evidence seems to be leaning towards CRRT over hemodialysis. He discussed the US ATN and the Australia & New Zealand RENAL studies, both of which are designed to answer the question as to which modality is superior, if any (results likely late this year or early nesxt). I asked, as I invariably do, if anyone was yet paying attention to the GOOD things removed by all RRTs, and the likely very adverse effect this could have on critically ill patients. As one of the faculty noted, “I noticed your question either was not understood or ignored.” I’ve been interested in this issue since I started doing hemodialysis in the late 1970s. Despite several research proposals and countless times raising this issue, no one has ever responded in ANY way to this question and the literature in this area is poverty-stricken. I was a back-up speaker this year, so I did not give my proposed presentations. I am so frustrated over lack of attention to this issue that I am reproducing several slides from one of my unpresented presentations here:
As you can see, removal of amino acids (the only thing studied extensively) is enormous and relentless during HD. Keep in mind this is just amino acids! Many, many other molecules are no doubt removed as well. It must be far worse during CRRT modalities in that circulating concentrations are probably continuously lower, particularly with hemodialfiltration. How critically ill patients can heal, let alone thrive, under conditions where circulating arginine, glutamine, ascorbate, nitrite (and many other) critical molecules are continuously depleted is amazing in and of itself. We know RRT is “good” at removing wastes, why would it be any less effective at removing nutrients and vital regulatory molecules?
Jeff Lipman reviewed antibiotics in RRT and listed those most commonly underdosed and discussed the importance of the unique pharmacodynamic characteristics of these drugs to their bacterial killing ability. He noted that with beta-lactamases it is important to maintain the blood concentration at 4 to 5 times the MIC for the majority of the dosing interval and that his work had recently demonstrated that resolution of infection is faster with continuous, as opposed to bolus dosing, with ceftriaxone. One reason Veerappan selected Jeff was because he perceives a problem with many clinicians failing to take into account the need to adjust dosing of non-protein bound antibiotics based on the patient’s wet (as opposed to dry) weight. Unfortunately, Veerappan failed to tell Jeff about this, and the topic was not a focus of the talk. So, my bet is that Jeff can count on being invited to speak at Manchester sometime in the future ;-).
Tom Bleck was very well used and gave four talks: Neurological Causes of Difficulty in Weaning, Steroids – Are They Doing Harm, Neurogenic Pulmonary Edema, and Sub-Arachnoid Hemorrhage – What is New? All of these talks were excellent. The Neurogenic pulmonary edema talk laid out the mechanics as currently understood, and provided a good overview of treatment options.
Bleck is probably the only man on earth who can get up before an audience of critical care professionals and say something positive about steroids in the setting of neuroinjury. He provided very insightful discussion about the pharmacology of various steroids and (to me) invaluable insight about the failure of the clinical trials of the Lazardoids (21-aminosteroids), a class of drugs which shone in animal models of neuroinjury, but failed (as all such drugs have) in the clinic. Perhaps some day it will be understood that drugs can be invaluable while being utterly useless when given alone. IMHO, the Lazaroids probably have an important role to play in neuroprotection when used in combination with other molecules.
And that brings me to Professor Mitch Fink who gave three riveting presentations on basic science advances in sepsis: The Role of HMGB-1 in Critical Care, Epithelial Dysfunction, and Novel Pharmaological Agents for Mitochondrial Protection. I’m only going to discuss the HMGB-1 and mitochondrial protection talks. High mobility group box protein 1 (HMGB-1) is a ubiquitous protein in nucleated mammalian cells which is released in response to, and as a result of, injury. In rodent models of sepsis, inhibition of HMGB-1 release or its neutralization by polyclonal antibodies rescues the animals even late in sepsis (day 2). Interestingly, HMGB-1 levels remain elevated in animals and humans long after recovery from the septic or traumatic insult. Dr. Fink noted that levels were still at or near their acute phase peak in community acquired pneumonia patients even after discharge from hospital. This suggests that HMGB-1 has a complex signaling role and that its mechanics will be sophisticated. Inhibition of HMGB-1 will probably be critically related to timing, and it may be the case that inhibition of downstream signaling could be more effective. Dr. Fink noted that HMGB-1 is probably like TNF in the complexity of its actions and that it should not be seen as the” magic bulle”t in sepsis or shock. However, as he pointed out, while TNF antibodies did not prove useful in sepsis, they have virtually revolutionized the treatment of rheumatoid arthritis, and may do so for Chron’s disease as well.
The mitochondrial protection paper reviewed his recent work on targeted delivery of the SOD mimetic TEMPOL to the mitochondria. TEMPOL is water soluble and does not penetrate cell or mitochondrial membranes rapidly. One solution to this is to attach TEMPOL to mitochondrially transported moieties from the old antibiotic Gramicidin. I had two slides dealing with these molecules in my “Ideal Fluids” presentation so it was very rewarding to get to talk at length with Dr. Fink about these compounds and his related work with the free radical scavenger ethyl pyruvate (EP). Dr. Fink noted that ethyl pyruvate failed an initial clinical trial to reduce inflammation in cardiopulmonary bypass and that the intellectual property rights had been returned to UPMC, making near-term further development of EP for clinical application in resuscitation solutions much less likely.
Also of great interest was the emphatic assertion by Dr. Fink that the much touted media results of pharmacological induction of metabolic inhibition by hydrogen sulfide and carbon monoxide were very real and very likely to have a revolutionary impact on emergency and critical care medicine. Sabo Czabo (of PARP and NOS fame) recently left Inotek Pharmaceuticals in Cincinnati to take a position with Mark Roth’s Ikaria, the company Roth helped create to exploit application of pharmacological metabolic inhibition (i.e., hypothermia in a molecule) in CCM. Mitch noted that Ikaria has raised almost $700 million dollars and has major support from DARPA (Defense Advanced Research Projects Agency Defense Advanced Research Projects Agency) the US military’s agency aimed at making warfare 100% survivable (for “us” not “them). Ikaria now controls most of the IP related to pharmacologic induction of reduced metablolism, including acquisition of Scanlan and Grandy”s thyronomines — molecules capable of inducing a hibernation like state. A number of my slides dealt with H2S and they are included below:
What matters most to many people attending a conference is the added value of the locale. The experience of the cultural, culinary, and social life of the target city is the big attraction. Manchester is certainly not London, and thank heavens it is not San Francisco, either. So, while there are good restaurants, a fine air and space museum, and one of the largest collection of Alma Tadema’s paintings anywhere (I have a soft spot for Tadema) it not the place to come for a sophisticated night on the town.
What unarguably matters to everyone who attends a conference is that the venue be accommodating, and the food be good. Bad service, logistic failures, and above all bad food and drink, can devastate a meeting. So far, Veerappan has done well above average in this respect, with truly excellent conference planning and execution (none of the usual ghastly failures such as bollixed slide projectors, clueless hotel staff, screeching sound systems, etc.). Service was very good, and the luncheon food was delicious and varied – vastly better than the usual hellish over-cooked vegetables, macerated chicken, and starchy-sauce-drenched fare served at meetings the world over.
Britain has changed more than I dreamed possible. I hosted two conferences in Britain (London) in the mid-1980s and they were the single worst meeting logistic and dining nightmares I’ve ever experienced. The food was (literally) inedible, the staff was rude at worst, and completely uncaring at best. Finding hospitable restaurants with edible food was a chore. All that has changed. Even the basic supermarket food at Tesco or Sainsbury’s is a religious experience, compared to what is available in the US outside of major, cosmopolitan cities like New York and San Francisco. There is actually edible bread here in England (everwhere in England), good cheeses, and truly wonderful (not frozen) heat and eat meals which are better than most of the best restaurant fare in what has become the vast culinary wasteland that is now America. The evening dinner at the Palace Hotel was above average, and the wine flowed liberally, as did the conversation. So, if you want a seamless meeting experience where good food and accommodation substantially enhance the experience, come to the Manchester meeting.
I was blessed to sit at the dinner tables with CCM luminaries (Tom Bleck, Mitch Fink, Mervyn Singer, Jean Louis Vincent, and Christaain Boerma, among others) and now can say I’ve broken bread with someone who had tea with the Queen (quite a good story from Mervyn Singer from his medical school days). However, a real highpoint of the meeting for me was the two dinners Veerappan and his wife Mina hosted in their home. Veerappan and Mina are ethnic Tamil, and the region he and his wife come from in India was formerly known as Madras. Need I say more? If you have never heard the words “Madras Curry,” then, sadly, you have not yet eaten the food of gods. Both nights the fortunate guests were served home made Indian cuisine and allowed to mix and mingle in relaxed surroundings. Conversation was heavily oriented towards “shop talk” and it was apparent that most of the guests were very intellectually engaged. BTW, at least for me, lunches were the same, with my fellow diners showing both enthusiasm for, and preoccupation with, the medical topics of interest to them.
Alas, A. Liolios was not at this year’s meeting, so I spent my nights in the hotel instead of on wild expeditions around the city. Sadly, even a good book cannot compare with a 4-hour foot search for a good sushi restaurant and a up-end digital video camera retailer on a Saturday night in Manchester.
One lunch, regrettable hurried, was with Christiaan Boerma who did a beautiful presentation on the microcirculation. Christiaan is using orthogonal polarization spectral (OPS) imaging to create real-time motion pictures of the microcirculation f the intestine and sublingual mucosa of high resolution and clarity.
He has been able to do this on septic patients undergoing bowel resection, so, for the first time, we have been able to get a look at the microvilli in human sepsis.
The pictures were breathtaking. It is possible to see the arterioles, venules and capillaries as they dynamically perfuse the villi, and no still picture can even begin to do justice to the numerous video clips Christiaan showed during his presentation.
Indeed, the still photo above can be misleading if it is not understood that microcirculatory flow in septic animals (and the humans observed so far) is very heterogenous — some areas show normal or slightly aberrant autoregulation and flow whilst they situated only a few tens, or hundreds of microns, away from other areas where flow is severely compromised, or dysfunctional. Similarly, sublingual and intestinal mucosal blood flows, and blood flow patterns, may be very different from those observed in the microvilli of the same patient.
This microcirculatory dysfunction can be virtually abolished by administration of 0.5 mg of nitroglycerine (NGT) after appropriate fluid/pressure resuscitation:
This strongly suggests that the sludging and autoregulatory disturbances observed are NO mediated. Dobutamine had a dramatic negative effect on microcirculation, whereas, by contrast, Dobutrex (5 micrograms/kg/min) improved microcirculatory flow almost as much as NTG (De Backer,Crit Care Med 2006; 34:403-408.):
Clearly, being able to miniaturized this imaging system and deploy it endoscopically and laprascopically to dynamically monitor end organ perfusion/resuscitation could be invaluable. Not surprisingly, there is a strong correlation with outcome (survival) in successful versus unsuccessful resuscitation of the microcirculation (Trzeciak, Ann Emerg Med 2007; 49:88-98):