Critical Care - Latest Comments

Oxygen consumption and lactic acidosis

Heikki Savolainen — 2010-02-22T00:00:00Z

Dear Editor,

The interesting investigation shows that the biguanidine treatment interferes with the oxygen consumption (1). This is compatible with the fact that eg. metformin is an inhibitor of the functions of complex I in the mitochondrial respiratory chain (2).

The association with the lactic acidosis is less straightforward as the drug increases the D-lactic acid production (3) which is not subject to the same physiological regulation as L-lactate.

The increased formation of D-lactate is probably due to the increased methylglyoxal production from glucose.

The clearance of D-lactate is slow as it is oxidized by a high Km D-lactate oxidase in the mitochondria. Thus, the acidosis associated with it is of longer duration. It should be remembered that protons also hamper the mitonchondrial respiration so that this is an additional factor in the decrease in the oxygen consumption.

1 Protti et al. Critical Care 2010; 14: R22

2 Zmijewski et al. Am J Resp Crit Care Med 2008; 178: 168

3 Talasniemi et L. Clin Biochem 2008; 41: 1099

Amino acid imbalance and encephalopathy

Heikki Savolainen — 2010-02-12T00:00:00Z

Dear Editor,

This investigations shows that infusion of LPS may alter the brain uptake of amino acids. It is thought that this may be a contributing factor to the clinical encephalopathy analogously to effects of hyperammonemia (1).

One wonders whether this is due to an effect on the amino acid transporter across the blood-brain barrier (2) or whether it reflects changes in the circulation due to increased NO.

The postulated contributory role of amino acids would be more convincing if glutamate or glycine uptake would be specifically affected.

1 James JH, Jeppson B, Ziparo V, et al. Hyperammonemia, plasma amino acid imblanace and blood-brain amino acid transport. A unified theory of portal systemic encephalopathy. Lancet 1979; ii: 772

2 Smith QR, Momma S, Aoyagi M, et al. Kinetics of neutral amino acid transport across the blood-brain barrier. J Neurochem 1987; 49: 603

Vitamin D is also useful for septicemia

William B. Grant — 2010-02-12T00:00:00Z

This is a great paper.

Related to their finding is that vitamin D reduces the risk of septis/septicemia, in part through induction of cathelicidin and defensins, which have antibiotic and antiendotoxin properties, in part through shifting cytokine production from proinflammatory to less or non-inflammatory ones. A similar benefit was recently reported for pneumonia following A/H1N1 pandemic influenza infection in the United States in 1918-19.

Thus, the combination of fish oil and vitamin D could go a long way towards reducing the incidence and death of people from sepsis/septicemia. It might be worthwhile to consider giving those entering the hospital for operations 50,000 IU of vitamin D each of several days prior to or shortly after the operation if they are thought to have low serum 25-hydroxyvitamin D levels.

References
Grant WB. Solar ultraviolet-B irradiance and vitamin D may reduce the risk of septicemia. Dermato-Endocrinology. 2009;1(1):37-42.
http://www.landesbioscience.com/journals/dermatoendocrinology/article/7250/

Grant WB, Giovannucci D. The possible roles of solar ultraviolet-B radiation and vitamin D in reducing case-fatality rates from the 1918–1919 influenza pandemic in the United States. Dermato-Endocrinology 2009;1(4): 215-9.
http://www.landesbioscience.com/journals/29/article/9063/

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 Apr 23;7:28.

Mookherjee N, Hancock RE. Cationic host defence peptides: innate immune regulatory peptides as a novel approach for treating infections. Cell Mol Life Sci. 2007 Apr;64(7-8):922-33.

Mookherjee N, Rehaume LM, Hancock RE. Cathelicidins and functional analogues as antisepsis molecules. Expert Opin Ther Targets. 2007 Aug;11(8):993-1004. Review.

Statistical Concerns in Analysis of Adiponectin and Cortisol Data

Allan Walkey — 2009-12-03T00:00:00Z

We read with interest the report by Venkatesh et al investigating changes in adiponectin during critical illness. Results show a significant relationship between adiponectin concentration and cortisol levels in critically ill subjects (eg., an R2 of 0.32 with p=0.01 at day 3). Upon further review of the data we observed that one extreme outlier exists in the cortisol day 3 data set (level 2620 nmol/L, with all other values below 600 nmol/L). As the authors point out, this outlier skews the cortisol data to a non-parametric distribution. Thus, in this case, the use of a simple linear regression to analyze the relationship between adiponectin and cortisol violates the normality assumptions needed for valid linear regression analyses. More appropriate analyses of these data would include reporting the Spearman correlation coefficient (as mentioned in Methods section) or log-transformation of the data for linear regression analysis. Performing these analyses, we found the Spearman correlation coefficient for the relationship between adiponectin and cortisol to be 0.51 with p=0.17; alternatively, linear regression with log-transformed values led to an R2=0.06 with p=0.33. Results demonstrate that when using non-parametric statistical methods, the relationship between adiponectin and cortisol at day 3 is no longer statistically significant. Despite this, we agree with the authors conclusion that “the relation between adiponectin and the inflammatory response, organ dysfunction and outcome in critical illness” is a subject worthy of future investigations.

Sincerely,

Allan Walkey, MD

Ross Summer, MD

Routine use of weaning preditors: better if we go faster

Sergio Nemer — 2009-11-06T00:00:00Z

Sérgio N. Nemer and Carmen S.V. Barbas

We thank Dr. Epstein for his interest in our article. We also thank him for his interesting comments and considerations. We agree that the great majority of weaning predictors presented only moderate accuracy in predicting the weaning outcome. Although, some integrative indexes, like the frequency to tidal volume ratio (f / Vt ratio) [1] and the ratio of airway occlusion pressure to maximal inspiratory pressure (P 0.1 / MIP) [2], have already presented the accuracy higher than the other single parameters [1,2].
In the Evidence-Based Guidelines for Weaning and Discontinuing Ventilatory Support [3], eight parameters presented statistically significant likelihood ratio to predict the outcome of a ventilator discontinuation in more than one study. As 15% of the patients who can complete a SBT require reintubation in the following 48 hours after extubation [4], clinical impression is so inaccurate [3] and at least eight parameters for weaning were considered accurate, we think that there are no reasons of not considering the weaning predictors.
We also know and agree with Dr. Epstein that weaning predictors are really useful in a presence of favorable clinical condition, although, this one alone did not reflect the respiratory mechanics, the inspiratory endurance and other factors that are important too. Several patients with favorable clinical condition are reintubated as a consequence of these factors.
In a Statement of the Sixth International Consensus Conference on Intensive Care Medicine [4], patients that presented favorable clinical condition and weaning predictors like f / Vt ratio in less than 105 breaths / minute / liter, respiratory frequency in less than or equal 35 breaths / minute, MIP in less than or equal to 20 – 25 cmH2O, vital capacity in more than 10 ml / kg, tidal volume in more than 5 ml/kg should be considered ready for weaning. So, our opinion is that the combination of a favorable clinical condition with favorable weaning predictors leads to more probability for a successful weaning. We think that there is no consensus about the recommendation of weaning predictors and that it is a very polemic topic, but the two weaning consensus [3,4] are not contrary to the weaning parameters, and there are other important revisions, wrote by Dr Tobin, the expert on this theme, that recommend the weaning predictors, mainly the f/Vt ratio [5,6]. Is so hard to find one research about weaning that do not consider the f/Vt ratio, once this one is incorporated in the daily practice in the great majority of the intensive care units.
The f/Vt ratio is the more popular [5] and the most or one of the most accurate weaning predictor [7]. Another great advantage of the f/Vt ratio is its feasibility. In our study [8], the new index that we developed showed to be the most accurate weaning predictor among the parameters evaluated, even when compared to the f/Vt ratio. Regarding the consideration of extubation failure and spontaneous breathing trial (SBT) failure (or weaning failure) as the same outcome, it is important to emphasize that if one patient that tolerated SBT and was extubated but, after some hours needed reintubation, it does not necessarily mean that the reason of extubation failure had been related to the capacity of protecting the airway. As cited in our manuscript, the study of Frutos-Vivar et al [9] presented 13.4% (121 of the 900 patients) of extubation failure related to f/Vt ratio, positive fluid balance 24 hours prior extubation and presence of pneumonia at the beginning of mechanical ventilation. In our study, no patient was reintubated as a consequence of laryngeal edema, copious secretion, ineffective cough or other reason related to the capacity to protect the airway. Among the 10 reintubated patients in our study, all of them were like that as a consequence of reasons related to the respiratory system (as fatigue, hypoxemia and rapid shallow breathing), not to the capacity of protecting the airway. When a patient present a extubation failure as a consequence of inability to protect the airway, the signs are so clear, like a stridor, that developed sometimes immediately after the extubation. So, the definitions about weaning failure and extubation failure present factors that could be present in both of them and should not be separated until the inability to protect the airway had been clearly proved. SBT is not a perfect test and there are patients that tolerate short SBTs but not longer ones without reasons related to the capacity to protect the airway. So, we see no reasons why not classifying our 54 patients as weaning failure, even that 10 of them had been reintubated, once there were no reasons related to the capacity of protecting the airway. We agree with Dr. Epstein that the reasons related to the capacity to protect the airway cannot be detected by weaning predictors, because in this situation, the signs of respiratory distress are presented only after the extubation. So, we do not have the intention to prove that our IWI can detect extubation failure related to the capacity of protecting the airway, but we showed that our IWI was accurate in detect extubation failure without reasons related to the capacity to protect the airway in 9 of 10 patients. It is true that this is a small number of events that preclude meaningful analysis, but once more, we do not have the intention to prove that our IWI can detect extubation failure related to the airway protection. However, we also hope to detect patients that are extubated but cannot tolerate 48 hours after extubation without reasons related to the airway protection. Even though 10 of the 54 weaning failure patients had been reintubated in our study, the reason of failure was basically the same and in reality, all of them failed. We think that these definitions should be revised, because not all patients that are reintubated are related to the airway protection.
We do not hope that our IWI can change the recommendations about weaning predictors, because in our opinion, these ones are not discouraged and they are only polemical. We hope that with the accuracy of our index, weaning predictors like our IWI and the f/Vt ratio could be more used and more credited. We still think that the f/Vt ratio remains as one of the best weaning predictors and should be considered for weaning. We think that our IWI can be used routinely in the great majority of the intensive care units. In order to prove the accuracy of our IWI, it will be a pleasure that prestigious authors like Dr. Epstein and Dr. Tobin could use our index one day and prove its accuracy.

References
1. Yang KL and Tobin MJ: A prospective study of indexes predicting the outcome of trials of weaning from mechanical ventilation. N Engl J Med 1991, 324: 1445–1450.
2. Capdevila XJ, Perrigault PF, Perey PJ, Rouston JPA and d’Athis F: Occlusion pressure and its ratio to maximum inspiratory pressure are useful predictors for successful extubation following T-piece weaning trial. Chest 1995, 108: 482-489.
3. MacIntyre NR, Cook DJ, Ely WE, Epstein SK, Fink JB, Heffner JE, Hess D, Hubmayer RD, Scheinhorn DJ: Evidence-Based Guidelines for Weaning and Discontinuing Ventilatory. Chest 2001, 120: 375S-395S.
4. Boles J-M, Bion J, Connors A, Marsh B, Melot C, Pearl R, Silverman H, Stanchina M, Vieillard-Baron A and Welte T: Weaning from mechanical ventilation. Eur Respir J 2007, 29: 1033-1056.
5. Tobin MJ and Jubran A: Meta-analysis under the spotlight: focused on meta-analysis of ventilator weaning. Crit Care Med 2008, 36: 01-07.
6. Tobin MJ: Advances in mechanical ventilation. N Engl J Med 2001, 344: 1986-1996.
7. Vassilakopoulos T, Zakynthinos S and Roussos C: The tension-time index and the frequency / tidal volume ratio are the major pathophysiologic determinants of weaning failure and success. Am J Respir Crit Care Med 1998, 158: 378–385.
8. Nemer SN, Barbas CSV, Caldeira JB, Carias TC, Santos RG, Almeida LC, Azeredo LM, Noé RA, Guimarães BS, Souza PC: A new integrative weaning index of discontinuation from mechanical ventilation. Crit Care 2009, 13:R152.
9. Frutos-Vivar, Ferguson ND, Esteban A, Epstein SK, Arabi Y, Apezteguía C, González M, Hill NS, Nava S, D’Empaire G: Risk Factors for Extubation Failure in Patients Following a Successful Spontaneous Breathing Trial. Chest 2006, 130: 1664-1671.

Detecting bacterial versus non-bacterial febrile illnesses in the emergency room

Francisco Arnalich — 2009-10-01T00:00:00Z

Dear Sir
I read with interest the paper by Y. Paran et al. proposing the use of C-reactive protein velocity (CRPv), defined as the ratio between CRP value on admission and the number of hours since the onset of fever, to distinguish febrile bacterial infections from non-bacterial febrile illnesses in patients admitted to the emergency room (ER). The diagnostic accuracy of CRPv expressed as AUC was better than for CRP alone (0.871 vs. 0.783), and similar to that reported by using six different biomarkers, including CRP and PCT, which yielded an AUC of 0.88 (1). Despite their study´s strengths, however, some limitations not stated by authors deserve consideration. First, the results are not valid for patients with dementia or other mental diseases which are unaware of fever or unable to provide informed consent. Second, they did not include febrile outpatients who were normothermic at the ER because of ongoing antipyretic treatment. In addition, it would be interesting to monitor changes in CRP over the period of 6 to 12 hours, which represents the average length of stay for clinical work-out in the ER. Unlike procalcitonin secretion which peaks 8 h after stimulation, CRP peaks only after 36 h and allows a time-course analysis. The magnitude of change on two measurements adds information to that obtained by the CRP velocity, especially in patients for whom the time of fever onset is doubtful. In the Emergency Department at La Paz Hospital, Madrid, Spain, a 1100-bed academic tertiary hospital serving 485.000 inhabitants, we usually measured CRP levels on admission and 6 hours afterwards. We have found that patients with proven bacterial infections had an average two-fold increase in CRP levels over the admission values compared with a mean 0.6-fold increase in patients with non-bacterial febrile illness. We think that combining information from CRP velocity and CRP increases over 6 to 12 hours is a cost-efficient approach to identify patients with bacterial infection.

1)Kofoed K, Andersen O, Kronborg G, Tvede M, Petersen J, Eugen-Olsen J, Larsen K. Use of plasma C-reactive protein, procalcitonin, neutrophils, plasminogen activator receptor, and soluble triggering receptor expressed on myeloid cells-1 in combination to diagnose infections: a prospective study. Crit Care 2007; 11:R38.

Lactic acid transporters

Heikki Savolainen — 2009-08-13T00:00:00Z

Dear Editor,

The excellent commentary summarizes the ideas how to approach the problem of hyperlactatemia (1). L-lactic acid is a physiological source of energy e.g. for brain which is why cell membranes have several isoforms of monocarboxylate transporters for its uptake(2).

It seems that in case of inadequate oxidative phosphorylation, excessive amounts of L-lactate is produced. Large L-lactate concentrations seem to inhibit its own uptake (3) thus increasing the extracellular pool.

A special case is the D-lactate, e.g. from hyperglycemia or propylene glycol containing drugs (4). While taken up by the transporters its metabolism is slow by the mitochondrial D-lactate oxidase leading to clinical acidosis as well.

1 Gutierrez G, Williams JD. The riddle of hyperlactatemia. Crit Care 2009; 13: 175.

2 Settle P, Mynett K, Speake P, et al. Polarized transport activity and expression in the syncytiotrophoblast of the term human placenta. Placenta 2004; 25: 496.

3 Majumdar S, Gunda S, Pai D, et al. Functional activity of monocarboxylate transporter, MCT1, in the human retinal pigmented epithelium cell line, ARPE-19. Mol Pharm 2005; 2: 109.

4 Talasniem JP, Pennanen S, Savolainen H, et al. Assay of D-lactate in diabetic plasma and urine. Clin Biochem 2008; 41: 1099.

Many facets of bacterial meningitis

Heikki Savolainen — 2009-07-28T00:00:00Z

Dear Editor,

The authors rightly point out the central role of macrophages in the severe meningitis. They are also the important source of NO associated classically with the dilatation of blood vessels at 4-20 nM concentrations. Larger, 100-340 nM nitrogen oxide concentrations compete with oxygen at the cytochrome oxidase thereby adding a histotoxic component to the inflammation (Antunes et al, 2004).

Thus, one wonders what all modalities of a treatment aimed at the macrophage functions might be.

Antunes A, Boveris A, Cadenas E. Proc Ntnl Acad Sci USA. 2004; 101: 16774.

Ventilator-associated tracheobronchitis after major heart surgery: a plea for a randomized trial

Saad Nseir — 2009-07-13T00:00:00Z

I read with interest the article by Dr. Hortal and colleagues [1]. The authors are to be congratulated for conducting such a large multicentre study on the incidence of and risk factors for ventilator-associated pneumonia (VAP) after major heart surgery. Using modified CDC criteria to define ventilator-associated tracheobronchitis (VAT), the incidence rate of VAT was 3.7 per 1000 days of mechanical ventilation. If we consider only the patients with more than 72 hours of mechanical ventilation, 10.6% (7 of 66) developed VAT. Of these seven patients, two developed a VAP later on. The mean CPIS of the patients with VAT was 5.0 (1.7) points and the median number of days on mechanical ventilation at the time of VAT was five days (IQR = 3-6). Patients with VAT required mechanical ventilation during a median of 11 days (IQR = 8-25). These data merit further comment.
VAT is an intermediate processes between tracheobronchial colonization and VAP [2]. The most frequently used definition for VAT is fever (>38° C) with no other recognizable cause, purulent sputum production, positive culture of respiratory specimen at significant threshold, and no radiographic signs of new pneumonia [3]. This definition has been validated by previous studies [4-6], and was accepted by a recent European expert statement [7]. The incidence of VAT found by the authors is in line with previous studies [4]. Interestingly, the study by Hortal and colleagues is the first prospective multicentre study to validate this definition of VAT in patients undergoing major heart surgery.
Some clarifications would be helpful to determine the impact of VAT on outcome in this population. Authors stated that 28% of VAT patients developed subsequent VAP. However, was VAT a risk factor for subsequent VAP? Further, could the authors compare mortality, duration of mechanical ventilation, and ICU stay between VAT patients, VAP patients, and patients without ventilator-associated lower respiratory tract infection?
Authors stated that in their opinion the use of anticipative or pre-emptive antimicrobial therapy should be explored as one of the few potential interventions to avoid VAP in the high-risk population. However, antimicrobial treatment is a well known risk factor for multidrug-resistant bacteria emergence [8]. Therefore, a targeted antibiotic therapy for VAT may be a new paradigm for VAP prevention and better patient outcomes [9]. Did all patients with VAT receive antimicrobial treatment? Was there any difference in subsequent VAP rate between patients who received antibiotics and those who did not? Two recent randomized studies, performed in patients with VAT [3,10], demonstrated that aerosolized and systemic antibiotics reduced subsequent VAP rate, and increased mechanical ventilation-free days, weaning and ICU-survival. Whether a short course of antibiotics in VAT patients could reduce VAP rate and improve outcome after major heart surgery should be determined by future randomized studies.

REFERENCES

1. Hortal J, Munoz P, Cuerpo G, Litvan H, Rosseel PM, Bouza E: Ventilator-associated pneumonia in patients undergoing major heart surgery: an incidence study in Europe. Crit Care 2009, 13:R80.
2. Nseir S, Ader F, Marquette CH: Nosocomial tracheobronchitis. Curr Opin Infect Dis 2009, 22:148-153.
3. Nseir S: Aerosolized antibiotics for ventilator-associated tracheobronchitis: let's go with the flow! Crit Care Med 2008, 36:2191-2192.
4. Nseir S, Di Pompeo C, Pronnier P, Beague S, Onimus T, Saulnier F, Grandbastien B, Mathieu D, Delvallez-Roussel M, Durocher A: Nosocomial tracheobronchitis in mechanically ventilated patients: incidence, aetiology and outcome. Eur Respir J 2002, 20:1483-1489.
5. Nseir S, Favory R, Jozefowicz E, Decamps F, Dewavrin F, Brunin G, Di Pompeo C, Mathieu D, Durocher A: Antimicrobial treatment for ventilator-associated tracheobronchitis: a randomized, controlled, multicenter study. Crit Care 2008, 12:R62
6. Valencia M, Ferrer M, Farre R, Navajas D, Badia JR, Nicolas JM, Torres A: Automatic control of tracheal tube cuff pressure in ventilated patients in semirecumbent position: a randomized trial. Crit Care Med 2007, 35:1543-1549.
7. Torres A, Ewig S, Lode H, Carlet J: Defining, treating and preventing hospital acquired pneumonia: European perspective. Intensive Care Med 2009, 35:9-29.
8. Nseir S, Di Pompeo C, Diarra M, Brisson H, Tissier S, Boulo M, Durocher A: Relationship between immunosuppression and intensive care unit-acquired multidrug-resistant bacteria: a case-control study. Crit Care Med 2007, 35:1318-1323.
9. Craven DE: Ventilator-associated tracheobronchitis (VAT): questions, answers, and a new paradigm? Crit Care 2008, 12:157.
10. Palmer LB, Smaldone GC, Chen JJ, Baram D, Duan T, Monteforte M, Varela M, Tempone AK, O'Riordan T, Daroowalla F, Richman P: Aerosolized antibiotics and ventilator-associated tracheobronchitis in the intensive care unit. Crit Care Med 2008, 36:2008-2013.

Sepsis 14 Calculation Worksheet

Christophe Adrie — 2009-06-11T00:00:00Z

A calculation worksheet "Sepsis 14" allowing an easy use of the "Model for predicting short-term mortality of severe sepsis" is available on our website:
http://www.outcomerea.org/ehtm/sepsis/

Outcomerea Study Group