Critical Care - Latest Comments

Metformin-induced effects in oxygen consumption

Heikki Savolainen — 2012-05-14T14:10:55Z

Dear Editor,

The authors of this study have to be congratulated for their elegant experiments and reaching the correct conclusions.

The drug is, in fact, an inhibitor of the complex I in the mitochondrial respiratory chain. This seems to be the main reason for the deleterious effects. Two other circumstances may, however, contribute and aggravate it. D-lactate produced excessively from glucose is slowly metabolized by the D-lactic acid oxidase prolonging the metabolic acidosis, and acidotic excessive protons impair the the terminal cytochrome oxidase which is essentially a proton pump to molecular oxygen.

Thus, metformin interferes with the oxidative phosphorylation at several stages.

Low serum 25(OH)D concentrations may explain the findings regarding IL-6, hyperglycemia and glucose control in septic patients

William B. Grant — 2012-05-14T10:18:16Z

The paper by Nakamura et al. [1] reported correlations between interleukin-6 (IL-6) level, hyperglycemia, and glucose control and outcomes of septic patients. Those with failed glucose control had poorer survival rates than those with successful glucose control. Those with failed glucose control had higher IL-6 levels and much higher rates of septic shock.

The findings are consistent with lower 25-hydroxyvitamin D [25(OH)D] concentrations for those with failed glucose control. Vitamin D shifts cytokine production from T-helper 1 (Th1) to Th2 types, which includes reducing IL-6 levels [2]. Serum 25(OH)D concentrations have been found inversely correlated with glucose concentrations [3]. However, treatment with vitamin D seems to be able to increase insulin secretion but may have little impact on glucose control [4]. Thus, the effects of vitamin D deficiency may act over an extended period to reduce glucose control. More importantly, serum 25(OH)D concentrations have been found inversely associated with sepsis [5] and those with lower serum 25(OH)D concentrations have poorer survival with sepsis and other conditions in intensive care units [6-8]. The mechanism whereby vitamin D reduces risk and severity of sepsis is through induction of cathelicidin (LL-37) by the 1,25-dihydroxyvitmin D metabolite [2]. Cathelicidin is considered an antisepsis molecule [9].

The 25(OH)D concentration required for optimal health is at least 40 ng/ml (100 nmol/l) [10]. Based on the link between low serum 25(OH)D concentration and sepsis, increasing serum 25(OH)D concentrations for those diagnosed with sepsis may be beneficial. According to one paper, ¿Theoretically, pharmacological doses of vitamin D (2,000 IU per kg per day for three days) may produce enough of the naturally occurring antibiotic cathelicidin to cure common viral respiratory infections, such as influenza and the common cold, but such a theory awaits further science.¿ [10]. Vitamin D3 is much more effective than is vitamin D2 [11]. Vitamin D3 can now be prescribed in 50,000 IU doses [12].

While the evidence presented in this comment supports use of vitamin D in treating those with sepsis, such treatment should still be considered experimental and should be done in conjunction with standard medical practice.

References
1. Nakamura M, Oda S, Sadahiro T, Watanabe E, Abe R, Nakada T, Morita Y, Hirasawa H. Correlation between high blood interleukin-6 level, hyperglycemia and glucose control in septic patients. Critical Care 2012, 16:R58 (11 April 2012)
2. Khoo AL, Chai LY, Koenen HJ, Oosting M, Steinmeyer A, Zuegel U, Joosten I, Netea MG, van der Ven AJ. Vitamin D(3) down-regulates proinflammatory cytokine response to Mycobacterium tuberculosis through pattern recognition receptors while inducing protective cathelicidin production. Cytokine. 2011 Aug;55(2):294-300.
3. Hirani V. Relationship between vitamin D and hyperglycemia in older people from a nationally representative population survey. J Am Geriatr Soc. 2011;59:1786-1792.
4. Thomas GN, Scragg R, Jiang CQ, Chan W, Marz W, Pilz S, Kim HC, Tomlinson B, Bosch J, Lam TH, Cheung BM, Cheng KK. Hyperglycaemia and vitamin d: a systematic overview. Curr Diabetes Rev. 2012;8:18-31.
5. Jeng L, Yamshchikov AV, Judd SE, Blumberg HM, Martin GS, Ziegler TR, Tangpricha V. Alterations in vitamin D status and anti-microbial peptide levels in patients in the intensive care unit with sepsis. J Transl Med. 2009;7:28.
6. Ginde AA, Camargo CA Jr, Shapiro NI. Vitamin D insufficiency and sepsis severity in emergency department patients with suspected infection. Acad Emerg Med. 2011;18:551-554.
7. Youssef DA, El Abbassi AM, Cutchins DC, Chhabra S, Peiris AN. Vitamin D deficiency: implications for acute care in the elderly and in patients with chronic illness. Geriatr Gerontol Int. 2011;11:395-407.
8. Flynn L, Zimmerman LH, McNorton K, Dolman M, Tyburski J, Baylor A, Wilson R, Dolman H. Effects of vitamin D deficiency in critically ill surgical patients. Am J Surg. 2012;203:379-382; discussion 382.
9. Mookherjee N, Rehaume LM, Hancock RE. Cathelicidins and functional analogues as antisepsis molecules. Expert Opin Ther Targets. 2007;11:993-1004.
10. Cannell JJ, Hollis BW. Use of vitamin D in clinical practice. Altern Med Rev. 2008;13:6-20.
11. Heaney RP, Recker RR, Grote J, Horst RL, Armas LA. Vitamin D3 Is more potent than vitamin D2 in humans. J Clin Endocrinol Metab. 2011;96:E447-E452.
12. Cannell J. Bio-Tech 50,000 IU D3 now available for prescription. 28 Feb. 2012. http://www.vitamindcouncil.org/bio-tech-50000-iu-d3-now-available-for-prescription/

Steroid timing and the implication for the future septic shock trial

wei huang — 2012-03-09T09:10:39Z

Dear editor,
the debates regarding the effects of stress-dose steroid in septic shock patients have long been triggering since the treatment be firstly introduced. So far, we still not very clear whether a key point or points exist for the successful steroid treatment. In our opinion, Dr. Kyeongman Jeon and his colleagues[1] just prove that timing of steroid cast predominant influence on the septic shock patient¿s outcomes .
According to the ¿surviving sepsis campaign¿ guideline[2], stress-dose steroid therapy should be initiated only ¿when hypotension remains poorly responsive to adequate fluid resuscitation and vasopressors¿. However, failure in fluid resuscitation and supporting therapies with vascular active drugs for septic shock patients actually indicate the vulnerable patient¿s hemodynamic situation and global organ perfusion already be very instable and even destroyed, therefore, definitely be link to the a serials of harmful outcomes. With this respect, it is quiet questionable that a ¿delayed¿ steroid therapy, other than a ¿early¿ choice, be recommended in international guideline.
Moreover, There were already many comparisons and interpretations for the different results between Prof. Annane¿s study[3] and CORTICUS trial[4]. We noticed Annane and his cooperators initiated steroid within 3-8 hours of the onset of septic shock symptom and randomization, which very same as Dr. Kyeongman Jeon study(mean 6.5 hours) . By contrast, CORTIUCS investigators started that within 72h, ¿as defined by a systolic blood pressure of less than 90 mm Hg despite adequate fluid replacement or a need for vasopressors for at least 1 hour¿. Theoretically, it is reasonable that exacerbation in hemodynamic parameters last as long as 24-72 hours may easily associated with higher mortality rate in septic shock patients, regardless which drug they prefer after that.
In summary, we believe that Dr. Kyeongman Jeon and previous Prof. Annane¿s studied already highlight tracks we should explore further to rescue our patients. And it is also a very important implication for the future investigations targeting steroid in septic shock, for example, ADRENAL trial(NCT01448109)in Australia and new Zealand. The beneficial effects of aggressive steroid therapy may hide in early treating stage of septic shock.
Reference:
1.Park HY, Suh GY, Song JU, Yoo H, Jo IJ, Shin TG, Lim SY, Woo S, Jeon K: Early initiation of low-dose corticosteroid therapy in the management of septic shock: a retrospective observational study. Crit Care 2012,16:R3.
2.Dellinger RP, Levy MM, Carlet JM, Bion J, Parker MM, Jaeschke R, Reinhart K, Angus DC, Brun-Buisson C, Beale R, Calandra T, Dhainaut JF, Gerlach H, Harvey M, Marini JJ, Marshall J, Ranieri M, Ramsay G, Sevransky J, Thompson BT, Townsend S, Vender JS, Zimmerman JL, Vincent JL: Surviving Sepsis Campaign: international guidelines for management of severe sepsis and septic shock: 2008. Crit Care Med 2008, 36:296-327.
3.Annane D, Sebille V, Charpentier C, Bollaert PE, Francois B, Korach JM, Capellier G,Cohen Y, Azoulay E, Troche G, Chaumet-Riffaud P, Bellissant E: Effect of treatmentwith low doses of hydrocortisone and fludrocortisone on mortality in patients with septic shock. JAMA 2002, 288:862-871.
4.Sprung CL, Annane D, Keh D, Moreno R, Singer M, Freivogel K, Weiss YG, Benbenishty J, Kalenka A, Forst H, Laterre PF, Reinhart K, Cuthbertson BH, Payen D, Briegel J: Hydrocortisone therapy for patients with septic shock. N Engl J Med 2008, 358:111-124.

units used

Marlène Bouillon — 2012-03-09T09:10:01Z

Usually, most experts agree that levels less than 20 ng/ml (50 nmol/L) 25(OH)D are considered deficient and levels between 20 to 30 ng/ml ( 50 to 75 nmol/L) are insufficient, as reported in your references 10-12. It is possible that you make a mistake, since you express all your results as ng/dL ?

Study classification within a systematic review of prone ventilation

David Noble — 2012-03-09T09:09:19Z

Dear Editor,

I note the study of Mancebo et al has been classified by Abroag et al (Table 1) as one that used "protective lung ventilation".
The study of Mancebo et al commenced in 1998 before "ARDSnet" was published. These authors state that up to 10ml/kg of (actual) body weight and up to 35 or 40cm of water for a plateau pressure was considered acceptable. The accompanying supplement to that paper indicates that even these targets were breached in over 10% of cases.
Can the study of Mancebo et al really be classified as one that used "lung protective ventilation"?

Glucose and lactate as brain energy sources

Heikki Savolainen — 2012-03-09T09:08:00Z

Dear Editor,

This highly significant study shows that insulin administration can diminish cerebral glucose concentration. This effect may be partially ameliorated by the circumstance that L-Lactate can serve as an alternate energy source (1). Furthermore, lactate concentration in blood may rise with the increased intake of glucose in the cells.

Would it not be interesting to follow the cerebral L-lactate metabolism in patients under critical care?

1 Rinholm JE, Hamilton NB, Kessaris N, et al. Regulation of oligodendrocyte development and myelination by glucose and lactate. J Neurosci 2011; 31: 538-548

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.