Sepsis: pathophysiology and clinical management
BMJ 2016; 353 doi: https://doi.org/10.1136/bmj.i1585 (Published 23 May 2016) Cite this as: BMJ 2016;353:i1585
Chinese translation
该文章的中文翻译
All rapid responses
Rapid responses are electronic comments to the editor. They enable our users to debate issues raised in articles published on bmj.com. A rapid response is first posted online. If you need the URL (web address) of an individual response, simply click on the response headline and copy the URL from the browser window. A proportion of responses will, after editing, be published online and in the print journal as letters, which are indexed in PubMed. Rapid responses are not indexed in PubMed and they are not journal articles. The BMJ reserves the right to remove responses which are being wilfully misrepresented as published articles or when it is brought to our attention that a response spreads misinformation.
From March 2022, the word limit for rapid responses will be 600 words not including references and author details. We will no longer post responses that exceed this limit.
The word limit for letters selected from posted responses remains 300 words.
Dear Sir,
I would like to congratulate Dr. Walid Al-Wali.
And most important is the message of Prof. Cleary and Prof. Rohde:
Streptococci are intracellular microbes.
You will not find them by swab.
And the the blood-stream infection by streptococci is only the tip of the iceberg of not diagnoses streptococcal infections.
And the best treatment is penicillin.
Best wishes
Yours Friedrich Flachsbart
Lit.:
J. J. Ferretti, D. L. Stevens, V. A. Fischetti: Streptococcus pyogenes: Basic Biology to clinical manifestations. (Internet)
University of Oklahoma Health Sciences, 2016.
http://www.ncbi.nlm.nih.gov/books/NBK333432/
M. Rohde, P. P. Cleary: Adhesion and invasion of Streptococcus pyogenes into host cells and clinical relevance of intracellular streptococci.
a. a. O.
http://www.ncbi.nlm.nih.gov/books/NBK333420/
Competing interests: No competing interests
We have found the article of Jeffrey Gotts and Michael Matthay very helpful. But in order to fully optimize antimicrobial treatment the following points should be observed:
• Ideally appropriate antimicrobials should be started within the first hour and choice of antimicrobial agent is influenced by local antimicrobial guidelines and sensitivity patterns.
• It is imperative that recent or previous microbiology culture results and susceptibility patterns are checked as this will influence choice of antimicrobials used.
• Checking for recent or previous alert organisms i.e. multi-drug resistant bacteria such as Meticillin-Resistant Staphylococcus aureus (MRSA) ,ESBL-producing organisms ,Carbapenemase-Producing Enterobactericeae (CPE) and Glycopeptide-Resistant Enterococci (GRE) is also equally important. The reason being that they would need to be targeted as part of the antimicrobial therapy, as they may be the infective agents, and also the choice of agents used should not lead to their selection as they may potentially subsequently lead to healthcare associated infections which are difficult to treat because of their multi-antimicrobial resistant nature.
• When empirical broad-spectrum antimicrobial agents are used initially when the infective agent is not known, once a significant infective organism is identified then therapy should be de-escalated to mono-spectrum targeted agents which are equally if not more effective but also they have much less collateral damaging effect i.e. are less likely to disturb the microbial flora and lead to the emergence of multi-antimicrobial resistant organisms in addition to super-infection such as the occurrence of Clostridium difficile infections. An example is when Streptococcus pyogenes is isolated as a cause of necrotizing fasciitis then good practice is to switch to high doses of benzyl-penicillin in addition to clindamycin rather than continuing using piperacillin/tazobactam, cephalosporins or carbapenems. Another example is switching to benzyl penicillin in the case of pneumococcal pneumonia and stopping the broad-spectrum antimicrobials.
Competing interests: No competing interests
We appreciate Dr. Shanbhag’s thoughtful response to our review. Because the focus of our review was sepsis (the systemic response to infection), space restrictions did not permit much emphasis on particular organisms or sites of infection nor precise antibiotic selection. We agree that dental abscesses, and skin and soft tissue infections generally, are an important cause of both minor and life-threatening infections. We also agree that there are many interesting potential molecular targets for sepsis therapies, and note that thrombomodulin, selepressin, and levosimendan appear in Figure 7, which summarizes many of the large ongoing clinical trials in sepsis. The reference provided for methylthiouracil (Kwak et al.) is a study in mice, and we are unaware of any safety or efficacy data for this drug in patients with sepsis. Thrombomodulin is approved for therapy of DIC in Japan, where a Phase III study [1] was conducted in a mixed population of 234 patients with DIC from infection or hematologic malignancy and with a primary outcome of improved coagulation parameters relative to treatment with heparin (no difference in mortality was seen). As shown in Figure 7, an international Phase III placebo-controlled trial of thrombomodulin in patients with sepsis and coagulopathy is now enrolling, with a primary outcome of 28 day mortality and anticipated completion in 2018.
1 Saito H, Maruyama I, Shimazaki S, et al. Efficacy and safety of recombinant human soluble thrombomodulin (ART-123) in disseminated intravascular coagulation: results of a phase III, randomized, double-blind clinical trial. J Thromb Haemost JTH 2007;5:31–41. doi:10.1111/j.1538-7836.2006.02267.x
Competing interests: No competing interests
Just as GPs are starting to get to grips with the triggers for recognising sepsis markers using objective measurements and when GP medical software providers have just made available programs that monitor inputed examination values generating warning prompts to clinicians, we are told that these markers have been cast aside. The article may be of great value to hospital clinicians but seems to offer no advice to Primary Care other than to cast doubt on the value of our recently adopted practice. Could the authors shed some light on best practice in Primary Care?
Competing interests: No competing interests
The work of Grotts et al is instructive (1). However in discussing the genetic factors involved in sepsis the authors notably overlook the role of inherited mitochondrial DNA haplogroups. Mitochondrial DNA (mtDNA) is inherited exclusively maternally unlike chromosomal DNA which has both paternal and maternal origin. An Increasing body of evidence is accumulating that patient mitochondiral DNA haplogroup is an important determinant of survival following sepsis (2,3,4,5). Prospective multicentre studies have shown that haplogroups H and JT confer a very strong survival advantage in the context of sepsis.The mechansim by which this effect operates remains to be definitively elucidated. However it is suspected that certain mtDNA haplogroups may be more metabolically efficient in sepsis, generating sufficient energy to overcome infection; while not being so overzealous in their response that they cause harm. Alternatively certain haplogroups may be less inflammagenic when liberated from damage cells in sepsis (2,3,4,5).
Hence the role of mitochondrial DNA is important in sepsis. It may account to some degree for both the heritability of the phenomenon but also the recent seminal finding of increased late mortality in sepsis survivors compared to matched controls(6). Identifying those at high risk and those at low risk will faciliate risk-stratification and aid in the pursuit of interventions that will improve outcomes for all.
1. Gotts JE, Matthay MA.Sepsis: pathophysiology and clinical management. BMJ. 2016 May 23;353:i1585
2. Baudouin SV, Saunders D, Tiangyou W, Elson JL, Poynter J, Pyle A, Keers S, Turnbull DM, Howell N, Chinnery PF.
Mitochondrial DNA and survival after sepsis: a prospective study. Lancet. 2005 Dec 17;366(9503):2118-21
3. Lorente L, Iceta R, Martín MM, López-Gallardo E, Solé-Violán J, Blanquer J, Labarta L, Díaz C, Borreguero-León JM, Jiménez A, Montoya J, Ruiz-Pesini ESevere septic patients with mitochondrial DNA haplogroup JT show higher survival rates: a prospective, multicenter, observational study. PLoS One. 2013 Sep 12;8(9):e73320. doi: 10.1371/journal.pone.0073320. eCollection 2013.
4. Lorente L, Iceta R, Martín MM, López-Gallardo E, Solé-Violán J, Blanquer J, Labarta L, Díaz C, Jiménez A, Montoya J, Ruiz-Pesini E. Survival and mitochondrial function in septic patients according to mitochondrial DNA haplogroup. Crit Care. 2012 Jan 17;16(1):R10.
5. Lorente L, Martín MM, López-Gallardo E, Ferreres J, Solé-Violán J, Labarta L, Díaz C, Jiménez A, Montoya J, Ruiz-Pesini E.Septic patients with mitochondrial DNA haplogroup JT have higher respiratory complex IV activity and survival rate.
J Crit Care. 2016 Jun;33:95-9. doi: 10.1016/j.jcrc.2016.02.003. Epub 2016 Feb 13.
6. Prescott HC, Osterholzer JJ, Langa KM, Angus DC, Iwashyna TJ. Late mortality after sepsis: propensity matched cohort study. BMJ. 2016 May 17;353:i2375.
Competing interests: No competing interests
The exhaustive clinical review by Gotts JE was read with interest (1). However, the author has glaringly failed to mention about dental causes for sepsis. Dental abscess which is nothing but the localized collection of pus at the apical area of the root of the teeth inside the alveolar bone has potential to cause sepsis (2). Bacterial endocarditis can result due to entry of odontogenic bacteria in the systemic circulation. It can be caused due to treatment procedures such as extraction of teeth, periodontal, endodontic and orthodontic procedures (3). Septic pulmonary embolism can be caused by dental infections such as periodontitis, periapical periodontitis and gingival abscess (4). Though dental sepsis is potentially life threatening it can be prevented (5). Metronidazole, clindamycin, penicillin, amoxicillin/ clavulate, imipenem/ cilastatin is helpful to manage sepsis associated with oral bacteria (1,4).
Additionally, it should be mentioned that recombinant thrombomodulin is helpful to manage pathogen-associated molecular patterns and damage-associated molecular patterns associated septic disseminated intravascular coagulation (6). Some of the additional emerging therapies for sepsis include the use of methylthiouracil, selepressin and levosimendan (7-9).
References
1. Gotts JE. Sepsis: pathophysiology and clinical management. BMJ 2016;353:i1585
2. Shweta, Prakash SK. Dental abscess: A microbiological review. Dent Res J (Isfahan). 2013;10(5):585-91.
3. Parahitiyawa NB, Jin LJ, Leung WK, Yam WC, Samaranayake LP. Microbiology of odontogenic bacteremia: beyond endocarditis. Clin Microbiol Rev. 2009;22(1):46-64
4. Shiota Y, Taniguchi A, Yuzurio S, Horita N, Hosokawa S, Watanabe Y, Tohmori H, Ono T; Okayama Respiratory Disease Study Group. Septic pulmonary embolism induced by dental infection. Acta Med Okayama. 2013;67(4):253-8.
5. Carter L, Starr D. Alarming increase in dental sepsis. Br Dent J. 2006;200(5):243.
6. Ito T. The role of thrombomodulin in sepsis-associated DIC. Rinsho Ketsueki. 2016;57(4):405-11.
7. Kwak S, Ku SK, Kang H, Baek MC, Bae JS. Methylthiouracil, a new treatment option for sepsis. Vascul Pharmacol. 2015; doi: 10.1016/j.vph.2015.07.013
8. Vincent JL. Emerging therapies for the treatment of sepsis. Curr Opin Anaesthesiol. 2015 Aug;28(4):411-6.
9. Heming N, Lamothe L, Ambrosi X, Annane D. Emerging drugs for the treatment of sepsis. Expert Opin Emerg Drugs. 2016;21(1):27-37.
Competing interests: No competing interests
Dear Sir,
40 years ago my clinical teachers showed me the wonderful impact of heparin on intravascular coagulation. (Prof. Kuhn, Göttingen.)
1981 the cardio-thoracic ICU of the university Göttingen was totally free of postoperative heparin.
Pulmonary and renal intravascular coaguation induced organ failure and consequent bleeding.
Heparin stopped this slippery slope to full blown sepsis.
I do not find heparin on your infographic of sepsis.
Best wishes
Yours
Friedrich Flachsbart
Lit.:
Flachsbart, F., Abdallah el-Sayed, B.:
Renale und pulmonale Funktionsstörungen nach Operationen am extracorporalen Bypass.
Göttingen, 1981
http://resolver.sub.uni-goettingen.de/purl?PPN548433445
Competing interests: No competing interests
Re: Sepsis: pathophysiology and clinical management
I read this article with interest but began to wonder whether modern medicine is more about rearranging the deckchairs on the Titanic. The first point the authors make, certainly in the paper version, is that sepsis has recently been redefined and it set me to thinking whether the constant redefinition of disease actually changes outcomes. It is certainly complicated as the authors show. Having opened the article by stating that severe sepsis is an old term not now used, the authors then go on to use it several times. We have over recent years redefined diabetes from juvenile and maturity onset, through insulin-dependent and non-insulin-dependent to type 1 and type 2, depression from reactive and endogenous through neurotic and psychotic to depression and major depression and chronic bronchitis and related conditions seemed to become chronic obstructive airways disease to chronic obstructive pulmonary disease. how does this verbose new nomenclature change outcomes?
Further, in the field of therapeutics a whole new, linguistically ignorant and ugly way of spelling drug names was forced upon us. Words like frusemide which used to trip off the end of the pen became more complicated and there was a widespread adoption of American spellings of drugs related to sulphur (sulphate becoming sulfate and so on) and so it went on. Again the question is the same? What evidence of improved outcomes is there as a result of this bureaucratic exercise?
Competing interests: No competing interests