Critical Care - Latest Comments

Importance of Metabolic Acidemia

Viktor Rosival — 2012-01-03T11:20:36Z

In the recent study of Jung et al [l] there are some discrepancies with the literature.

In the paragraph ¿Discussion¿, the authors write also ¿Whether metabolic acidemia is an etiologic contributor to organ dysfunction, or rather just a marker of illness has been debated¿. Several papers have reported negative influence of low blood pH on the level of consciousness; recently, these findings have been confirmed by Nyenwe et al [2]. The glycolytic enzyme phosphofructokinase is pH dependent, as its activity is decreasing with decreasing pH [3]. Therefore, brain cells cannot utilise glucose [4]. Where are published papers denying these results?

In the last sentence of their paper, the authors write ¿In 2011, there is no human study that has reported any beneficial or detrimental effect of sodium bicarbonate administration when facing severe mixed or metabolic acidemia ... .¿ Several papers have reported zero lethality of diabetic ketoacidotic coma if the treatment included infusions of alkalising solutions, e g [5]. Without alkalising solutions, lethality is up to 100%, e g [6]. Perhaps the decrease of lethality from 100% to zero% is a ¿beneficial effect¿?

Dr. Viktor Rosival, PhD,
SYNLAB department of laboratory medicine, Dérer's Hospital,
Limbová 5
SK-833 05 Bratislava,
Slovakia.
e-mail: rosivalv@hotmail.com

References

1. Jung B, Rimmele Th, Le Goff Ch, Chanques G, Corne Ph, Jonquet 0, Mailer L, Lefran J-Y, Guervilly Ch, Papazian L et al: Severe metabolic or mixed acidemia on intensive care unit admission: incidence, prognosis and impact of buffer therapy: a prospective, multiple-center study. Crit Care 2011, 15:R238
2. Nyenwe EA, Khan AE, Razavi LN, Wan JY, Kitabchi AE: Acidosis: The Prime Determinant of Depressed Sensorium in Diabetic Ketoacidosis. Diabetes Care 2010, 33:1837-1839
3. Trivedi B, Danforth WH: Effect of pH on the Kinetics of Frog Muscle Phosphofructokinase. J biol Chem 1966, 241:4110-4112.
4. Van Nimmen D, Weyne J,. Demeester G, Leusen I: Local cerebral glucose utilization in systemic acidosis. Am J Physiol 1984, 247:R639-R645.
5. Wagner A, Risse: A, Brill H-L, Wienhausen-Wilke V, Rottmann M, Sondern K, Angelkort B: Therapy of Severe Diabetic Ketoacidosis. Diabetes Care 1999, 22:674-677.
6. Basu A, Close CF, Jenkins D, Krentz AJ, Nattrass M, Wright AD: Persisting mortality in diabetic ketoacidosis. Diabet Med 1993, 10:282-284.

Misconception of Glycemic Control Algorithms

B. Wayne Bequette — 2012-01-03T11:19:29Z

Hoekstra and coworkers [1] review the technologies available for computerized glucose regulation in the intensive care unit, but misrepresent the differences between two control algorithms, Proportional-Integral-Derivative (PID) and Model Predictive Control (MPC). The differences between PID and MPC are illustrated by an example of an automobile on a roadway. They claim that the driver using MPC determines his/her driving strategy before departing, and maintains that trajectory throughout the trip. They also claim that the driver using PID makes frequent control action changes based on the difference between the ¿ideal¿ and actual trajectory. The MPC scenario shown is largely incorrect. MPC looks into the future (down the roadway) and determines the best sequence of control actions (driving strategy) to maintain that future trajectory. MPC does not simply implement that entire sequence of control actions (steering, braking, etc.), but, instead, updates the control actions at frequent intervals, in the same way that PID makes adjustments at frequent time intervals. Thus, the MPC strategy is no more sensitive to ¿small errors in input variables¿ than the PID strategy.

It has been a common misconception that PID is less sensitive than MPC to uncertainty in the system dynamics. In reality, MPC is no more sensitive to uncertainty than PID, if the two strategies are tuned for the same performance. Undergraduate textbooks [2] show that internal model control (IMC), a model-based control strategy, can be implemented as an equivalent PID controller when low-order models are used as the basis for controller design; this is also shown by Percival and co-workers [3]. The ¿take home message¿ is, if PID and MPC algorithms are tuned for the same level of performance, they have exactly the same sensitivity to uncertainty.

References

1. Hoekstra M, Vogelzang M, Verbitsky E, Nijsten MWN: Health technology assessment review: Computerized glucose regulation in the intensive care unit ¿ how to create artificial control. Critical Care 2009, 13:223 (doi:10.1186/cc8023)

2. Bequette BW: Process Control: Modeling, Design and Simulation. New Jersey: Prentice Hall; 2003.

3. Percival MW, Zisser H, Jovanovic L, Doyle III FJ: Closed-loop control and advisory mode evaluation of an artificial pancreatic b cell: Use of proportional-integral-derivative equivalent model-based controllers. J. Diabetes Sci Technol 2008, 2:636-644.

typo

Jon Borger — 2012-01-03T11:17:10Z

I believe the last sentence of the abstract is still incorrect, despite an apparent previous correction. It should read that SIMV is the "least" effective method of weaning.

Response of the authors

Laurent PAPAZIAN — 2011-11-08T16:35:16Z

Dr. Yegneswaran and Dr. Murugan did an interesting analysis of the ACURASYS trial. Some comments should however be made in order to clarify certain points.

The first point is that we did (and published) two physiological studies prior designing the ACURASYS trial(1,2). There was in both studies a strong tendency toward a better (and unexpected) outcome in the group of patients receiving cisatracurium. These two physiological studies were not designed to evaluate the outcome. For example the management of the patients was standardized only throughout the 120-h period of the studies. It would have however been logical to also include the second physiological study (1) in the metaanalysis. However this metaanalysis did not add useful and new elements because crude mortality at day 28 was significantly reduced in the cisatracurium group in the ACURASYS study (23.7% vs. 33.3%).
Second point, regarding the blinding of the healthcare providers, it must be highlighted that Ramsay score was at 6 when starting infusion of cisatracurium or placebo which precludes any movement of the patient(3). The blinding of all healthcare providers was not applied in our two first previous works(1,2) (only doctors were blinded) but there were some reviewers¿ criticisms regarding the absence of blinding for all health care providers. It was the reason why we planned this study using a double-blind design. Taking into account mortality as the main outcome rather than the duration of mechanical ventilation for example permitted to decrease the risks related to an unsatisfactory blinding. It would have been easier for us to design a study with ventilator-free days as the main outcome in order to show a better outcome effect of cisatracurium. However, the weaning from mechanical ventilation is more subjective and could be influenced by a potential inadequate blinding of the investigators. However we admit and we consider this criticism but we are waiting for some proposition for an alternative design¿.

The primary outcome was the proportion of patients who died before discharge home and within 90 days after study enrolment (day-90 mortality). Patients who were in other types of healthcare facilities and who were able to breathe spontaneously at 90 days were considered discharged home. It means that patients admitted in other types of healthcare facilities were also surveyed until day 90. This definition was also used in previously published studies by the ARDS network including ALVEOLI(4) and LaSRS(5).

The third point stressed by the two readers was the absence of biomarkers determination to explain beneficial effects of cisatracurium. This study has been done before(1). It is the one missed in the metaanalysis. There was a decrease of some pro-inflammatory cytokines in BAL and blood samples when the patients received 2 days of cisatracurium as compared with the placebo group.

In conclusion, it is a little bit reducing to regard the results of the ACURASYS trial as only related to the use of cisatracurium. The use of NMBA was part of a lung-protective policy including the use of low tidal volume, a proactive strategy regarding plateau pressure increases and, major point, a strong incitation to start weaning since day 3 when FiO2 was 0.6. or lower (see Table 1 of the article(3)).

We would like finally to thank Dr. Yegneswaran and Dr. Murugan to give us the opportunity to clarify some interesting points.

Laurent Papazian, Jean-Marie Forel et Antoine Roch

References
1 Forel JM, Roch A, Marin V et al. Neuromuscular blocking agents decrease inflammatory response in patients presenting with acute respiratory distress syndrome. Crit Care Med. 2006; 34(11):2749-2757.
2 Gainnier M, Roch A, Forel JM et al. Effect of neuromuscular blocking agents on gas exchange in patients presenting with acute respiratory distress syndrome. Crit Care Med. 2004; 32(1):113-119.
3 Papazian L, Forel JM, Gacouin A et al. Neuromuscular blockers in early acute respiratory distress syndrome. N Engl J Med. 2010; 363(12):1107-1116.
4 Brower RG, Lanken PN, MacIntyre N et al. Higher versus lower positive end-expiratory pressures in patients with the acute respiratory distress syndrome. N Engl J Med. 2004; 351(4):327-336.
5 Steinberg KP, Hudson LD, Goodman RB et al. Efficacy and safety of corticosteroids for persistent acute respiratory distress syndrome. N Engl J Med. 2006; 354(16):1671-1684.

Ambiguous primary endpoint and late trial registration

Jim Thornton — 2011-11-08T16:30:42Z

In addition to the potential bias, identified by the authors, arising from an open study and a subjective endpoint, I have two other worries.

The primary endpoint is reported as blood loss between T1 (time point 1) and two hours later. But T1 is described in different parts of the paper as either the time of delivery (Fig 1) or as the time of inclusion (text). Does "inclusion" mean randomisation or drug administration? If the staff recording blood loss ever took the time of drug administration in the treatment group as T1 they would be measuring blood loss over a shorter period than in controls.

Can the authors also explain why the date of trial registration on www.controlled-trials.com is dated 19 Feb 2011, three months after the trial paper was submitted to Critical Care, and three YEARS after the trial was completed! Can readers be confident that the primary endpoint, statistical methods and sample size were really pre-specified?

What were the hemoglobin levels?

David Whitlock — 2011-11-08T16:29:59Z

This is very interesting. I appreciate that the conventional wisdom is that O2 levels are all important, but what is also important is the balance of O2 vs NO. It is NO that tonally inhibits mitochondrial reduction of O2 to water by blocking cytochrome c oxidase from binding O2. It is not O2 consumption that is necessary for cells to survive, it is sufficient ATP levels. In sepsis, ATP levels are actually higher than during non-sepsis (for those who survive).[1]

In the vasculature, hemoglobin is the source of O2, but also the sink of NO. In sepsis, it is the very high NO levels which cause systemic vasodilatation. I hypothesize that the immune system generates such high NO levels during sepsis (via iNOS) to prevent the formation of bacterial biofilms. As bad as bacteria floating around in the blood stream are, biofilms on vessel walls are orders of magnitude worse. Because bacteria grow exponentially with a doubling time of ~20 minutes, effective suppression of biofilm, in the wild, must be very rapid.

The level of NO needed at the vessel wall to prevent bacterial adhesion comes from the balance between generation by immune cells, mostly in the extravascular space where the infection is, and its destruction by HbO2 in blood. The reaction of NO and HbO2 is first order with respect to both. The NO destruction rate depends on the product of the two concentrations. The NO level at the vessel wall is probably around 10 nM/L because sGC is producing lots of cGMP and so lots of vasodilatation. The NO generation rate to support a certain biofilm inhibiting concentration depends ~linearly on the hemoglobin level.

Isovolemic dilution of 50% (from 140 to 60 g/L) does not cause much drop in O2 levels in blood, SvO2 (77% to 73%) because there is compensatory vasodilatation, compensatory tachycardia and compensatory hyperdynamic circulation.[2] This compensatory vasodilatation occurs because the NO concentration goes up so the destruction rate matches the production rate. It is the produce of Hb concentration and NO concentration that stays constant. It needs to be appreciated that the important O2 level in blood is the chemical potential of O2, as measured by the partial pressure, not the ¿O2 content¿ in mL/L. O2 can only diffuse down a chemical potential gradient. If venous blood has a ¿normal¿ SvO2, then O2 delivery by the arterial blood is ¿normal¿. There is no deficit in O2 delivery, there may be a deficit in O2 consumption if NO levels are too high. This deficit cannot be corrected by supplying more O2. It needs to be corrected by reducing NO destruction and allowing normal regulation of extravascular NO to a lower level to occur, while maintaining biofilm inhibition at the vessel wall.

What controls how much O2 tissues take up is the NO levels in those tissues and how much that NO is blocking cytochrome c oxidase. High NO means high cytochrome c blockage and low O2 reduction and low ATP production by oxidative phosphorylation and so a requirement for high glycolytic ATP production.

Greater hemodilution means a lower NO level is needed in the extravascular space so the level at the vessel wall will be enough to inhibit biofilm formation, so mitochondria in the extravascular space see a lower NO level and so can generate more ATP via oxidative phosphorylation and so cells need less glucose to generate ATP via glycolysis (the reason for cachexia in sepsis). A molecule of glucose generates 19 times more ATP via oxidative phosphorylation than it does via glycolysis. Switching 5% of ATP production from oxidation to glycolysis requires delivery of twice as much glucose. If physiology can't do that, then ATP levels fall, mitochondria turn on, and self-destruct in the high NO environment.

My hypothesis is that the reduction of HbO2 mediated NO destruction is why hemodilution during sepsis has benefits in experimental animals.[3] The reduced destruction of NO, allows for a compensatory reduction in NO concentrations in the extravascular space and so there is less inhibition of cytochrome c oxidase in mitochondria and so there is more ATP generation by oxidative phosphorylation. This spares glucose for glycolytic ATP production which is necessary to maintain ATP concentrations above normal basal levels. Under this hypothesis, what causes multiple organ failure is the inability to maintain ATP levels via glycolysis, which causes ATP levels to fall, which causes mitochondria to turn-on, which in a high NO environment causes irreversible turn-off via nitration of MnSOD. [I discuss this in detail in 4]. When mitochondria try to operate in an NO environment that is too high, the mitochondria die, the cell dies, the organ dies and the organism dies.

A degree of hemodilution with fluids may actually be beneficial, even when SvO2 is high.

1. Brealey D, Brand M, Hargreaves I, Heales S, Land J, Smolenski R, Davies NA, Cooper CE, Singer M. Association between mitochondrial dysfunction and severity and outcome of septic shock. Lancet. 2002 Jul 20;360(9328):219-23.

2. Weiskopf RB, Viele MK, Feiner J, Kelley S, Lieberman J, Noorani M, Leung JM, Fisher DM, Murray WR, Toy P, Moore MA. Human cardiovascular and metabolic response to acute, severe isovolemic anemia. JAMA. 1998 Jan 21;279(3):217-21. Erratum in: JAMA 1998 Oct 28;280(16):1404. [see Figure 4]

3. Creteur J, Sun Q, Abid O, De Backer D, Van Der Linden P, Vincent JL. Normovolemic hemodilution improves oxygen extraction capabilities in endotoxic shock. J Appl Physiol. 2001 Oct;91(4):1701-7.

4. http://daedalus2u.blogspot.com/2008/06/mechanism-for-mitochondria-failure.html (accessed 06/28/2008).

Info

Mark Jason — 2011-11-08T16:28:31Z

Thank you for sharing such useful information. It contains that basic info which everyone should know.

Request for Clarification of Randomization Method

James Munis — 2011-08-16T17:29:57Z

Dear Editor,

While reviewing the literature on fluid responsiveness, including the article by Benes et al. (Critical Care 2010, 14:R118), I was struck by the similarity between the prospectively randomized groups in the demographics table (Table 2). In the words of one of our statisticians, "Of the 22 baseline characteristics presented in Table 2, only three had a p-value that was less than 0.500 The probability of this happening by chance is small (less than 1/1000)". Even a prospectively stratified study (which this was not - it was apparently randomized, not stratified, if I read the Methods correctly) would have difficulty achieving such balance across so many variables simultaneously. Perhaps I have misread the Methods, but I would appreciate clarification of Benes et al.'s randomization procedures.

Diagnostic tools in kidney damage

Heikki Savolainen — 2011-07-21T14:10:57Z

Dear Editor,

The elegant study by Prowle et al (1) shows that diminished diuresis is a good prognostic predictor. The kidney concentration capacity has been used as one of the earliest functional tests (2).

Renal (3) and extrarenal causes can cause oliguria and to understand them, determination of ion fluxes, erytrocytes and protein in the urine may be helpful (2). Altered excretion of proteoglycans in the urine are associated with frank proteinuria (4) and they may also be associated with a generalized capillary leak syndrome.

1 Prowle JR, et al. Oliguria as a predictive biomarker of acute kidney injury in critically ill patients. Crit Care 2011, 15: R17

2 Savolainen H. New uses for old urine tests. Brit J Ind Med 1989, 46: 361

3 Munshi R, et al. Advances in understanding ischemic acute kidney injury. BMC Med 2011; 9: 11

4 Savolainen H. A sensitive method for the analysis of urinary proteoglycans. Biochem Int 1992, 28: 475

RRT modalities

Jean-Michel Lannoy — 2011-06-07T12:54:49Z

Considering RRT modalities and own impact, it should be describe RRT technics (HD, CVVH, CVVHD, CVVHDF)performed for this study