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Drotrecogin alfa (activated) in severe falciparum malaria
Abstract
Drotrecogin alfa (activated) is a drug licensed for the treatment of severe sepsis. We describe the care of a 61-year-old man who developed multi-organ failure secondary to severe falciparum malaria infection with parasitaemia levels of 40%. Included in his care were an exchange blood transfusion and an infusion of Drotrecogin alfa (activated). Within hours of starting the infusion of Drotrecogin alfa (activated), the patient's clinical condition stopped deteriorating. Steady improvement followed with weaning from ventilatory assistance on day 14 post admission. The patient made a full recovery and was discharged home following rehabilitation. The indications for Drotrecogin alfa (activated) and the appropriateness of its use in severe malaria with multi-organ failure are discussed. Drotrecogin alfa (activated) may be a useful treatment in patients with multi-organ failure resulting from severe malaria.
... Newer adjuncts are needed because of the present high mortality rates and the limited benefit conferred by current ancillary therapies. Activated protein C (aPC) has anti-thrombotic, pro-fibrinolytic and anti-inflammatory properties and confers a relative mortality reduction of 22% in patients with severe sepsis and ≥ 2 organ dysfunction [4,5] and has recently been reported to be beneficial in severe falciparum malaria [6,7] and leptospirosis [7]. This is the first reported case of severe sepsis secondary to falciparum malaria with leptospirosis co-infection, with good response to aPC in addition to standard care. ...
... At the time of evaluation of this patient, a MEDLINE search and communication with manufacturers (Eli Lilly) revealed no reported data on the use of aPC in malaria or leptospirosis. Subsequently, five cases of successful use of aPC in severe malaria and one in leptospirosis has been reported [6]. This remains the first report of complicated dual infection treated with aPC. ...
... In contrast to sepsis of other aetiologies, the intense endothelial clogging by malaria and denudation due to leptospirosis may have contributed to a slower response. A similar delayed response has been observed in another reported case [6]. Large trials of use of aPC in malaria and leptospirosis, though urgently needed, are unlikely to be conducted given the costs involved. ...
Co-infection with falciparum malaria and leptospirosis is uncommon. The aim of this study is to report a case of severe sepsis secondary to dual infection with falciparum malaria and leptospirosis. The literature is also reviewed on the clinical course of such co-infections, and the possible mechanisms and treatment of patients with life-threatening malaria and leptospirosis with activated protein C. The patient was a 25-year old male admitted in the Respiratory Intensive Care Unit (RICU) with fever, haemolysis, acute renal failure, hepatitis, acute lung injury (ALI) and altered sensorium. A syndromic evaluation was done and investigations revealed falciparum parasitaemia. He was treated with parenteral artesunate, ceftriaxone and doxycycline, and adjunctive therapies as for severe sepsis. Infusion of activated protein C was started 20 hours after onset of organ dysfunction, and intensive haemodialysis was instituted. Over the next four days the patient became afebrile with progressive resolution of ALI, renal failure and hepatitis. His Leptospira serology (requested as part of the evaluation) was reported positive on day 5. Dual infections are common and under-recognized in the tropics. Failure to treat potential co-infections may lead to poor outcomes. Acute lung injury in falciparum malaria has high mortality rates and therapy as for severe sepsis may improve survival. Adjunctive therapies, including activated protein C, cannot replace source eradication.
... Au contraire, dans les formes sévères comme le neuropaludisme, l'activation de la coagulation est plus importante avec un score ISTH significatif [7] et des manifestations cliniques à type de saignements dans 10 % des cas [8], ce qui peut être observé lors d'une CIVD décompensée. La physiopathologie de la CIVD, notamment secondaire à un sepsis, est maintenant bien connue [10][11][12]. Le stimulus initiateur est l'exposition systémique et excessive de facteur tissulaire (FT) à la circulation sanguine : l'interaction de composés de la membrane bactérienne (lipopolysaccharides des bacilles à Gram négatif par exemple) avec des récepteurs spécifiques comme les Toll like receptors (TLR) induisent l'expression de FT au niveau des cellules endothéliales et des cellules de l'inflammation comme les monocytes, aboutissant à une génération très importante de thrombine. L'activation ou l'apoptose cellulaire (monocytes, plaquettes, cellules endothéliales) associée à la réponse inflammatoire est responsable de la formation de microparticules riches en FT et en phospholipides chargés négativement comme les phosphatidylsérines indispensables à la formation des complexes enzymatiques de la cascade de la coagulation. ...
... La survenue d'une gangrène au cours d'un paludisme est multifactorielle [4,5] et la CIVD est un de ces facteurs : dans la majorité des cas de gangrène décrits [4][5][6], il est retrouvé une CIVD associée (au moins 14 cas sur 18). La CIVD chez les cas décrits ne semble pas être majoritairement secondaire à une infection bactérienne [3,4,11], considérée comme la principale cause de CIVD dans le paludisme [2]. ...
... Des traitements thrombolytiques comme la streptokinase ont été utilisés, mais leur usage ne peut être recommandé du fait du risque hémorragique élevé chez des patients thrombopéniques [2]. De nombreuses autres stratégies thérapeutiques ont été testées [2][3][4]11], mais aucune n'a démontré une réelle efficacité. La compréhension des mécanismes de survenue d'une CIVD dans le paludisme et plus généralement dans le sepsis [11,12] permet d'envisager de nouvelles cibles thérapeutiques comme celles agissant sur la voie du FT [17,18] ou celles modulant la fonction endothéliale [19], afin de limiter l'apoptose endothéliale et de freiner l'activation de la coagulation et de l'inflammation responsables de la défaillance multiviscérale qui met en jeu le pronostic vital. ...
Peripheral gangrene with disseminated intravascular coagulation (DIC) during severe Plasmodium falciparum malaria has already been described but is unfrequent. We report here the case of a 62-year-old man admitted in the intensive care unit of our hospital for severe Plasmodium falciparum malaria with disseminated intravascular coagulation (DIC) and peripheral gangrene of his toes that needed amputation. Pathophysiological mechanisms leading to DIC in malaria can be used as a model to explain the relation between coagulation and inflammation. Therapeutic targeting of coagulation, by acting on inflammation, could be useful to limit the coagulation-inflammation cycle.
... It also binds specifically to neutrophils (Sturn et al. 2003), inhibits neutrophil adhesion to endothelial cells ( Grinnell et al. 1994) and reduces endotoxininduced neutrophil-dependent vascular injury in rats ( Murakami et al. 1996). In human sepsis, activated protein C is the only supportive therapy that is known to improve survival ( Bernard et al. 2001), while in human malaria, several case reports strongly suggest a beneficial effect for activated protein C (Kapadia & Shirwadkar 2006;Kendrick et al. 2006;Nau et al. 2006;Bruneel et al. 2007;Rankin & Austin 2007;Robak et al. 2010). ...
... A large randomized study has shown that administration of activated protein C improves survival in severe sepsis ( Bernard et al. 2001). In life-threatening P. falciparum malaria, several case reports describe marked clinical improvement after administration of activated protein C (Kapadia & Shirwadkar 2006;Kendrick et al. 2006;Nau et al. 2006;Bruneel et al. 2007;Rankin & Austin 2007;Robak et al. 2010). Therefore, the anti-apoptotic effects of activated protein C in both malaria and sepsis support the notion that activated protein C may offer clinical benefit not only in sepsis but also in severe malaria. ...
In malaria and sepsis, apoptotic endothelial damage is preventable in vitro by antioxidants and protease inhibitors. Activated protein C, which has anti-apoptotic effects, improves survival in sepsis. Therefore, we studied whether activated protein C prevents endothelial cell apoptosis, induced by serum from patients with malaria or sepsis.
Endothelial cells were incubated with patient sera (Plasmodium falciparum malaria, Escherichia coli sepsis, Staphylococcus aureus sepsis) or culture supernatants of the respective organisms, with or without neutrophils. Activated protein C was used to reduce endothelial cell apoptosis in vitro. The proportion of apoptotic endothelial cells was determined by TUNEL staining.
The apoptosis-inducing effect of patient sera or culture supernatants (P. falciparum, E. coli, S. aureus) on endothelial cells was augmented by neutrophils and reduced by activated protein C in the presence of neutrophils. Pre-incubating either endothelial cells or neutrophils with activated protein C also reduced the endothelial cell apoptosis rate. The pro-apoptotic effect of P. falciparum supernatant was reduced by pan-caspase inhibitor and caspase 8 inhibitor, but not by caspase 9 inhibitor. The pro-apoptotic effect of E. coli and S. aureus supernatants was also reduced by caspase 9 inhibitor.
Activated protein C protects vascular endothelial cells from apoptosis triggered by patient sera or culture supernatants in combination with neutrophils. It seems to act both on neutrophils and on endothelial cells. Activated protein C blocks caspase-8-dependent apoptosis, which accounts for endothelial damage in sepsis and malaria. Therefore, activated protein C might offer clinical benefit not only in sepsis but also in malaria.
... The TF-FVIIa inhibitors are known to prevent the coagulation of blood and have antiviral activity as shown in the case of SARS coronavirus (Du et al., 2007). Also, TF-VIIa coagulation cascade inhibitors are viewed as promising treatments for malaria, (Kendrick et al., 2006;Ruf, 2004), as studies indicate increased coagulation activity in malaria (G erardin et al., 2002;Ladhani et al., 2002). Furthermore, this study finds the phenyltriazolinones (PubChem ID: 104161460) and allosteric HCV NS5B polymerase thumb pocket 2 (PubChem ID: 163632044) inhibitors to be plausible inhibitors for the inhibition of the COVID-19 main protease, as these inhibitors interact with the His-41 and Cys-145 catalytic dyad in the COVID-19 main protease that has been found to be especially important in viral replication (Zhu et al., 2011). ...
Respiratory disease caused by a novel coronavirus, COVID-19, has been labeled a pandemic by the World Health Organization. Very little is known about the infection mechanism for this virus. More importantly, there are no drugs or vaccines that can cure or prevent a person from getting COVID-19. In this study, the binding affinity of 2692 protease inhibitor compounds that are known in the protein data bank, are calculated against the main protease of the novel coronavirus with docking and molecular dynamics (MD). Both the docking and MD methods predict the macrocyclic tissue factor–factor VIIa (PubChem ID: 118098670) inhibitor to bind strongly with the main protease with a binding affinity of −10.6 and −10.0 kcal/mol, respectively. The TF-FVIIa inhibitors are known to prevent the coagulation of blood and have antiviral activity as shown in the case of SARS coronavirus. Two more inhibitors, phenyltriazolinones (PubChem ID: 104161460) and allosteric HCV NS5B polymerase thumb pocket 2 (PubChem ID: 163632044) have shown antiviral activity and also have high affinity towards the main protease of COVID-19. Furthermore, these inhibitors interact with the catalytic dyad in the active site of the COVID-19 main protease that is especially important in viral replication. The calculated theoretical dissociation constants of the proposed COVID-19 inhibitors are found to be very similar to the experimental dissociation constant values of similar protease-inhibitor systems.
Communicated by Ramaswamy H. Sarma
... Thus, binding of PfEMP1 to EPCR results in an acquired functional PC system deficiency supporting the new paradigm that EPCR plays a central role in the pathogenesis of severe malaria. However, with the exception of a few case reports for beneficial effects of recombinant wt-APC (Xigris) treatment in severe malaria [38][39][40], no studies in patients or in animals in vivo have been performed and thus a direct contribution of EPCR to the pathogenesis of severe P. falciparum malaria in vivo remains to be established. Unfortunately, the lack of an animal model mimicking parasite host interactions that occur with P. falciparum in humans represents a major hurdle for addressing the role of EPCR in the pathogenesis of severe malaria. ...
Of the five Plasmodium species that infect humans, infection with P. falciparum is the most lethal, causing severe malaria syndromes, that result in over half a million annual deaths. With parasites becoming increasingly resistant to artemisinin there is an urgent need for new preventative and therapeutic options, for which understanding of the mechanisms that cause death and disability in malaria is essential. The recent discoveries that certain variants of P. falciparum erythrocyte membrane protein 1 (PfEMP1) expressed on infected erythrocytes are intimately linked to the precipitation of severe malaria syndromes and that these PfEMP1 variants contain EPCR binding domains provides new opportunities to improve our understanding of the molecular mechanisms responsible for the pathogenesis of severe malaria. EPCR is known for its essential role in the protein C (PC) system and for its ability to support the cytoprotective effects of activated protein C (APC) that result in vascular and tissue protective effects in many organ systems of the body, including the brain, lung, kidney, and liver. Observations that binding of PfEMP1 to EPCR results in an acquired functional PC system deficiency support the new paradigm that EPCR plays a central role in the pathogenesis of severe malaria. Thus, targeting of the PfEMP1-EPCR interaction and restoring the functionality of the PC system may provide new strategies for the development of novel adjuvant therapies for severe malaria.
... Moreover, there are no evidence-based guidelines on the use of ET in patients with severe malaria. 21,[24][25][26][27][28][29][30][31][32] There are some questions regarding how to perform ET appropriately. 3 The two methods used are the traditional manual ET approach and automated erythrocytapheresis. Manual ET was primarily used before 2000; the procedure is relatively time-consuming and may be associated with hemodynamic disturbances, which limit its use and may be a principal cause of the disagreements regarding the benefits and risks of the technique. ...
Although malaria is no longer endemic in Canada, it remains an important imported disease, principally among immigrants and travelers. The role of exchange transfusion in malaria treatment, in addition to standard anti-malarial treatment, remains controversial and is not well established. We report a case of severe malaria in a male traveler,complicated by multiorgan failure, septic shock, myositis, and unusual Streptococcus pneumoniae bacteremia.Manual exchange transfusion was used, in addition to artesunate-based therapy, and the patient responded well.This report shows that malaria remains an important differential diagnosis for travelers returning with fever and emphasizes the importance of prompt diagnosis and appropriate treatment.
... Despite the potentially critical importance of TNFα in the pathogenesis of severe complicated malaria, studies using monoclonal antibodies against TNFα had no impact on mortality [36,37]. The role of activated protein C concentrates in patients with malaria and DIC is unknown although the use of activated protein C has also been reported in patients with multi-organ failure from severe falciparum malaria [38,39]. However, this drug has recently been withdrawn due to the lack of confirmed benefit in follow up trials in severe sepsis [40]. ...
Blood coagulation activation is frequently found in patients with malaria. Clinically apparent bleeding or disseminated intravascular coagulation (DIC) is associated with very severe disease and a high mortality. Protein C, protein S, and antithrombin levels were found to be low in P. falciparum, but were normal in P. vivax infection. Plasma levels of plasminogen activator inhibitor-1 were high in cases of P. falciparum infection whereas tissue plasminogen activator levels were low. Elevated plasma levels of von Willebrand factor (vWF) and vWF propeptide, thrombomodulin, endothelial microparticles have been reported in P. falciparum-infected patients. It has been demonstrated that severe P. falciparum infection is associated with acute endothelial cell (EC) activation, abnormal circulating ultralarge vWF multimers, and a significant reduction in plasma ADAMTS13 function. These changes may result in intravascular platelet aggregation, thrombocytopenia, and microvascular disease. It has also been shown that P. falciparum-parasitized red blood cells (pRBCs) induce tissue factor (TF) expression in microvascular ECs in vitro. Recently, loss of endothelial protein C receptor (EPCR) localized to sites of cytoadherent pRBCs in cerebral malaria has been demonstrated. Severe malaria is associated with parasite binding to EPCR. The cornerstone of the treatment of coagulopathy in malaria is the use of effective anti-malarial agents. DIC with spontaneous systemic bleeding should be treated with screened blood products. Study in Thailand has shown that for patients who presented with parasitemia >30% and severe systemic complications such as acute renal failure and ARDS, survival was superior in the group who received exchange transfusion. The use of heparin is generally restricted to patients with DIC and extensive deposition of fibrin, as occurs with purpura fulminans or acral ischemia. Antiplatelet agents interfere with the protective effect of platelets against malaria and should be avoided.
... However, the facts that DC8 and other EPCR binding variants are preferentially expressed young children with limited malaria immunity 23,24 and the ubiquity of endothelial cells expressing EPCR, suggest that CIDRα1::EPCR-mediated P. falciparum cytoadhesion is the major virulence phenotype for severe malaria. Intriguingly, in a small number of case reports a recombinant form of APC (Xigris) [25][26][27] was used to successfully treat severe malaria infections with remarkable recoveries. The results presented here open new avenues for studies of malaria pathogenesis and possibilities for development of new adjunct therapy and vaccines to treat or protect children from malaria death. ...
Sequestration of Plasmodium falciparum-infected erythrocytes in host blood vessels is a key triggering event in the pathogenesis of severe childhood malaria, which is responsible for about one million deaths every year. Sequestration is mediated by specific interactions between members of the P. falciparum erythrocyte membrane protein 1 (PfEMP1) family and receptors on the endothelial lining. Severe childhood malaria is associated with expression of specific PfEMP1 subtypes containing domain cassettes (DCs) 8 and 13 (ref. 3), but the endothelial receptor for parasites expressing these proteins was unknown. Here we identify endothelial protein C receptor (EPCR), which mediates the cytoprotective effects of activated protein C, as the endothelial receptor for DC8 and DC13 PfEMP1. We show that EPCR binding is mediated through the amino-terminal cysteine-rich interdomain region (CIDRα1) of DC8 and group A PfEMP1 subfamilies, and that CIDRα1 interferes with protein C binding to EPCR. This PfEMP1 adhesive property links P. falciparum cytoadhesion to a host receptor involved in anticoagulation and endothelial cytoprotective pathways, and has implications for understanding malaria pathology and the development of new malaria interventions.
... It is indicated for use in patients with sepsis involving acute organ dysfunction who have a high risk of death. Two recent case reports provide evidence that APC may also be useful to treat multi-organ failure resulting from severe malaria (Kendrick, 2006;Srinivas, 2007). However, there is evidence that APC may cause bleeding in some patients, especially children and patients who have undergone recent surgery (Marti-Carvajal, 2007). ...
... 73 In view of similarities between severe malaria and severe sepsis syndrome, administration of recombinant-activated protein C has been tried in severe malaria in isolated cases. 82,83 Other adjuvant therapies such as mannitol, steroids, ironchelating agents (deferoxamine, deferiprone), N-acetyl cysteine, pentoxifylline, and so on have been tried but are of unproven benefit. 84 ...
Malaria remains a major health problem in much of Asia and Africa. A steady number of cases of imported malaria are also seen in many countries of the developed world. Plasmodium falciparum malaria and to some extent malaria caused by other species of Plasmodium can lead to many complications such as acute respiratory distress syndrome (ARDS), cerebral malaria, acute renal failure, severe anemia, thrombocytopenia, and bleeding complications. About 10% of patients with severe malaria die, usually as a result of multiorgan dysfunction. Critical care physicians should be aware of the complications and management of severe malaria. There has been significant progress in the understanding of pathogenesis of severe malaria over the last decade. Effective management of severe malaria includes early suspicion, prompt diagnosis, early institution of appropriate antimalarial chemotherapy, and supportive care, preferably in an intensive care unit. In this article, we review the different manifestations of severe malaria as relevant to critical care physicians and discuss the principles of laboratory diagnosis and management.
... The effectiveness of activated protein C as a treatment has not been systematically investigated. Case reports of patients with severe P. falciparum malaria infection improving following treatment with activated protein C [89,90] are insufficient to prove safety or efficacy in malaria at present. ...
Cerebral malaria (CM) is a life-threatening complication of Plasmodium falciparum infection and represents a major cause of morbidity and mortality worldwide. The nature of the pathogenetic processes leading to the cerebral complications remains poorly understood. It has recently emerged that in addition to their conventional role in the regulation of haemostasis, coagulation factors have an inflammatory role that is pivotal in the pathogenesis of a number of acute and chronic conditions, including CM. This new insight offers important therapeutic potential. This review explores the clinical, histological and molecular evidence for the dysregulation of the coagulation system in CM, looking at possible underlying mechanisms. We discuss areas for future research to improve understanding of CM pathogenesis and for the development of new therapeutic approaches.
... Therefore, malaria may provide a natural disease model for studying the interface between EC activation, inflammation and blood coagulation. Identification of TF as a potently critical mediator of malaria pathogenesis suggests that therapeutic agents targeted at TF and/or EC [75] might be useful as adjunct treatment in patients with severe disease [76]. ...
Plasmodium falciparum malaria infects 300-500 million people every year, causing 1-2 million deaths annually. Evidence of a coagulation disorder, activation of endothelial cells (EC) and increase in inflammatory cytokines are often present in malaria.
We have asked whether interaction of parasitized red blood cells (pRBC) with EC induces tissue factor (TF) expression in vitro and in vivo. The role of phosphatidylserine-containing pRBC to support the assembly of blood coagulation complexes was also investigated.
We demonstrate that mature forms of pRBC induce functional expression of TF by EC in vitro with productive assembly of the extrinsic Xnase complex and initiation of the coagulation cascade. Late-stage pRBC also support the prothrombinase and intrinsic Xnase complex formation in vitro, and may function as activated platelets in the amplification phase of the blood coagulation. Notably, post-mortem brain sections obtained from P. falciparum-infected children who died from cerebral malaria and other causes display a consistent staining for TF in the EC.
These findings place TF expression by endothelium and the amplification of the coagulation cascade by pRBC and/or activated platelets as potentially critical steps in the pathogenesis of malaria. Furthermore, it may allow investigators to test other therapeutic alternatives targeting TF or modulators of EC function in the treatment of malaria and/or its complications.
... The concept that TF is a potentially critical mediator of CM suggests that therapeutics targeting TF, and/or the endothelial cells may be successful in the treatment of malaria [154,288,289]. While anticoagulation in general might attenuate the local inflammatory escalation by reducing thrombin levels the antiinflammatory benefits of TF inhibition in particular are unique, as it blocks a proximal step of the coagulation cascade while levels of TNF-α—an important pathway for fighting infection—remains intact [154,288]. ...
Malaria remains a highly prevalent disease in more than 90 countries and accounts for at least 1 million deaths every year. Plasmodium falciparum infection is often associated with a procoagulant tonus characterized by thrombocytopenia and activation of the coagulation cascade and fibrinolytic system; however, bleeding and hemorrhage are uncommon events, suggesting that a compensated state of blood coagulation activation occurs in malaria. This article (i) reviews the literature related to blood coagulation and malaria in a historic perspective, (ii) describes basic mechanisms of coagulation, anticoagulation, and fibrinolysis, (iii) explains the laboratory changes in acute and compensated disseminated intravascular coagulation (DIC), (iv) discusses the implications of tissue factor (TF) expression in the endothelium of P. falciparum infected patients, and (v) emphasizes the procoagulant role of parasitized red blood cells (RBCs) and activated platelets in the pathogenesis of malaria. This article also presents the Tissue Factor Model (TFM) for malaria pathogenesis, which places TF as the interface between sequestration, endothelial cell (EC) activation, blood coagulation disorder, and inflammation often associated with the disease. The relevance of the coagulation‐inflammation cycle for the multiorgan dysfunction and coma is discussed in the context of malaria pathogenesis.
[Supplementary materials are available for this article. Go to the publisher's online edition of Microcirculation to access this free supplemental resource]
The majority of genetic variations in the human genome that lead to variety of different diseases are caused by non-synonymous single nucleotide polymorphisms (nsSNPs). Neurofibromatosis type 2 (NF2) is a deadly disease caused by nsSNPs in the NF2 gene that encodes for a protein called merlin. This study used various in silico methods, SIFT, Polyphen-2, PhD-SNP and MutPred, to investigate the pathogenic effect of 14 nsSNPs in the merlin FERM domain. The G197C and L234R mutations were found to be two deleterious and disease mutations associated with the mild and severe forms of NF2, respectively. Molecular dynamics (MD) simulations were conducted to understand the stability, structure and dynamics of these mutations. Both mutant structures experienced larger flexibility compared to the wildtype. The L234R mutant suffered from more prominent structural instability, which may help to explain why it is associated with the more severe form of NF2. The intramolecular hydrogen bonding in L234R mutation decreased from the wildtype, while intermolecular hydrogen bonding of L234R mutation with solvent greatly increased. The native contacts were also found to be important. Protein–protein docking revealed that L234R mutation decreased the binding complementarity and binding affinity of LATS2 to merlin, which may have an impact on merlin’s ability to regulate the Hippo signaling pathway. The calculated binding affinity of the LATS2 to L234R mutant and wildtype merlin protein is found to be 21.73 and −11 kcal/mol, respectively. The binding affinity of the wildtype merlin agreed very well with the experimental value, −8 kcal/mol.
Communicated by Ramaswamy H. Sarma
Malaria is a life-threatening disease, with its largest impact being due to Plasmodium falciparum infection in Africa. Military populations continue to be at a high risk of malaria and reported case series have frequently revealed poor compliance with preventative measures. The symptoms of malaria are non-specific and its management depends on awareness of the diagnosis and early recognition and treatment. This is aided by new and simple rapid diagnostic tests, but these should not replace the examination of blood films if these are available. Artemisinin combination therapy provides a more rapid and dependable cure of uncomplicated P falciparum infection, with artesunate now being the drug of choice in severe infection.
W. Conrad Liles – Division of Infectious Diseases, University of Toronto, Ontario, Canada
Acute response to LPS includes the release of a number of proinflammatory mediators that reach the brain in areas free of
blood-brain barrier, or via specific transport systems. The hypothalamic-pituitary axis is also activated via neural routes.
Then, infection is characterized by high circulating levels of adrenocorticotrope hormone (ACTH), and cortisol which remain
in plateau as long as the stressful condition is maintained. Circulating vasopressin levels follow a biphasic response with
high concentrations, followed by relative vasopressin insufficiency in about one third of cases. Early response to sepsis
is characterized by decreased serum T3 and increased rT3 levels. Serum T4 levels decrease within 24 to 48 h, and thyroid-stimulating
(TSH) levels remain normal, and have no more circadian rhythm. Prolonged sepsis is associated with centrally induced hypothyroidism.
In the initial response to sepsis, growth hormone levels are high with attenuated oscillatory activity and low insulin-like
growth factor (IGF)-1 levels. Later on, growth hormone (GH) secretion shows a reduced pulsatil fraction, and correlates with
low circulating levels of IGF-1. Exposure to endotoxin caused prompt increase in circulating adrenaline and noradrenaline
concentrations. Catecholamines have a very short half-life and are metabolized through captation, enzymatic inactivation,
or renal excretion. Plasma catecholamines levels remain elevated in plateau up to few months after recovery. Insulin levels
rapidly increased following LPS as a result of both increased secretion and tissue resistance. The clinical consequences of
the stress system activation include behavioral changes, cardiovascular, metabolic and immune adaptations.
The knowledge and skills obtained during the course of study in the medical school are insufficient to carry on a life-long
successful practice. To make clinical decisions, the practicing physician, even today is largely dependent on his obsolete
knowledge and expertise derived from unsystematic observations made during his training period, which can be as old as his
medical course itself. It needs to be updated periodically with the findings of new scientific/medical research. The scientific
research has to be translated into clinical practice for improving the patient care provided to the community. Patient’s values
are rarely acknowledged and current practices are often outdated, with the result that the patient rarely gets the best currently
available care. It is exactly 30 years since Archie Cochrane uttered the following words that sparked the “Evidence-Based
Medicine” movement: “It is surely a great criticism of our profession that we have not organized a critical summary, by specialty
or subspecialty, adapted periodically, of all randomized controlled trials” [1]. Today the practice of EBM has grown into the most popular paradigm or tool of translation of research into practice The
application of Evidence-Based Medicine (EBM) principles can help us with this daunting task that challenges us daily to offer
the “Best” patient care.
During the last 2 decades, an increased frequency of severe life-threatening infections caused by yeasts has been reported
in critical ICU patients [1]. The two main factors contributing to yeast infections are: the disregulation of immune system and the alteration of microbial
flora secondary to extensive use of broad-spectrum antibiotics. Critically ill patients exhibit a complex change in immune
function characterized by deactivation of macrophages and altered cellular response with shift from Th1 to Th2 response [1, 2]. Many other factors impairing the immune function during critical illness include hyperglycemia and the use of corticosteroids
[2]. In particular, corticosteroids have profound effects on the distribution and function of neutrophils, monocytes, and lymphocytes
and they directly stimulate the growth of some yeasts like Aspergillus fumigatus that have sterol binding proteins [2]. In ICU the two main fungal species involved in severe invasive infections are Candida spp. and Aspergillus spp., while Cryptococcus spp. remains a significant pathogen only in patients with severe immunodepression like those affected by HIV [1]. Invasive candidiasis affects around 2% of ICU patients in the USA, causing around 10% of ICU-acquired bloodstream infections
and representing the third commonest blood-stream pathogen [1]. However, the epidemiology of candidemia depends upon geographic region, ICU type, and case mix. The crude mortality associated
with candidemia ranges between 40 and 70%, depending on the severity of the underlying disease, while attributable mortality
estimates vary between 20 to 50% from retrospective studies and 5–7% from prospective clinical trials [3].
A rational resource allocation is today an imperative for intensive care medicine; resource allocation, in the intensive care
unit (ICU) context, is more related to human resources availability and organization, mainly the number of trained nurses,
than technology and supplies. For optimizing resources we must focus on redesigning and improving work processes. Adverse
events and medical errors have arisen as a formidable problem since November, 1999, when the US Institute of Medicine released
a report on medical error, “To Err is Human;” this publication was followed by several studies [1–4]. Technology complexity has improved patient prognosis but also has increased exponentially the possibility of errors and
adverse events.
Scientific research is in fact the systematic process of collecting and analyzing data in order to increase the available
knowledge on a specific field of interest. To start with it is mandatory that a protocol be established and understood by
all personnel involved in the research. This protocol must be approved by an Institutional Review Board (IRB) before the research
starts off. The research protocol is a formal written document specifying the study design and the manner in which it will
be conducted. It is the blueprint of the study and serves as a guideline throughout the implementation and analysis phases.
It details procedures to be followed yielding valid results. The research protocol fulfils scientific, ethical, and organizational
requirements so that the study may be conducted efficiently and according to the plan, thus standardizing the procedures for
research personnel to follow. The purpose of the study and the setting will determine which professionals will be consulted
about the development of the research protocol. Subject area experts, epidemiologists, and/or statisticians can be included.
Circulatory shock is the clinical syndrome corresponding to acute circulatory failure, and can arise from a number of disease
processes. The key feature of all forms of circulatory shock is an inability for tissues and cells to get enough oxygen in
relation to their oxygen needs, ultimately resulting in cell death. Circulatory shock thus represents a critical condition
where rapid and effective treatment can make the difference between life and death. In this chapter, we will briefly review
the definition and pathophysiological classification of shock, principles of monitoring in patients with shock, and general
management strategies.
The term “Critical Care Medicine” was first introduced in the late 1950s at the University of Southern California (USC) from
the concept that immediately life-endangered patients, the critically ill and injured, may have substantially better chances
of survival if provided with professionally advanced minute-to-minute objective measurements. Such measurements were largely
based on “real time” electronic monitoring of vital signs, hemodynamic and respiratory parameters, and complementary measurements
on blood and body fluids. Care was increasingly delegated to a new generation of dedicated physicians, professional nurses,
therapists, and clinical pharmacists in special care units. Since then, progress in the management of the acutely life-threatened
patient has been accelerated by rapid advances in both monitoring and measurement technologies and the interventions that
were triggered by them. Intubation and mechanical ventilation, hemodialysis, volume repletation guided by measurement of intravascular
pressures and cardiac output, resuscitation by the routine use of chest compression, defibrillation and pacemaker insertion
came into general use. These individual techniques had progressively evolved over the preceding decades by anesthesiologists
in the operating room and postanesthesia recovery units and by cardiologists in the catheterization laboratory. Conventional
methods of observation based on physical examination and largely manual measurement of vital signs at the bedside were therefore
increasingly superceded by electronic techniques of quantitative monitoring and measurements.
The key to infection control in the intensive care unit (ICU) is to appreciate that three different types of infection, due
to a limited range of potentially pathogenic micro-organisms (PPMs), six “normal” and nine “abnormal,” require a different
prophylactic maneuver. Primary endogenous infections can only be controlled by the immediate administration of parenteral
antibiotics, and secondary endogenous infections by the application of enteral antimicrobials in throat and gut. A high level
of hygiene and topical antimicrobials are required to control exogenous infections despite being less frequent [1–3] (Table 23.1).
The primary objective of intensive care is to prevent and treat secondary brain injury (SBI) caused by hypotension, hypoxia,
or hyperthermia. We will focus this chapter on traumatic brain injury (TBI) and our objective will be the treatment and prevention
of SBI using a neuroprotective strategy to maintain cerebral perfusion in order to meet the brain’s oxygen and metabolic demands.
Elevated intracranial pressure (ICP) is an important cause of SBI and associated with very poor outcome after TBI. Elevated
ICP can be related to brain edema, vascular engorgement, cerebral contusion, or intracranial mass lesions. The prevention
and control of raised ICP and the maintenance of cerebral perfusion pressure (CPP) are essential therapeutic goals after TBI.
ICP monitoring has developed an essential role in the treatment of TBI, despite the incredible absence of class-1 studies
and its use is only recommended by international consensus guidance [1].
The intensive care unit (ICU) is generally considered as part of the hospital where patients are treated during an acute severe
illness or after acute major injury. However, the ICU is also a common place of death with 1 in 5 Americans dying during or
just after an ICU admission [1]. Advances in modern medicine have altered the dying process such that many deaths in hospital, and particularly in the ICU
[2–5], are preceded by an end-of-life decision, a decision to withdraw or withhold life-supporting therapy. There is no specific
definition of “end-of-life,” but it is generally considered to be the period during which it is recognized that a patient
has a terminal process and that further treatment will offer no benefit, and to be the transition period from cure to comfort
[6]. The decisions surrounding end-of-life on the ICU are often complex because they are affected not only by medical factors,
but also by multiple personal aspects, including individual preferences, religion, and cultural influences. The influence
of family and friends in such decisions can also be considerable. Some recommendations for end-of-life care have been published
in the USA [7] and by several national medical societies, but there remains considerable variability in the approach to end-of-life care
and decision making at an international, national, and even local level.
The Surviving Sepsis Campaign (SSC), an initiative of the European Society of Intensive Care Medicine (ESICM), the International
Sepsis Forum (ISF), and the Society of Critical Care Medicine (SCCM), was developed in 2002 in a global effort to improve
the management, diagnosis, and treatment of sepsis. The three planned phases of the SSC reached a conclusion in December 2008,
but the ideas created continue to impact on the daily management of the patient with severe sepsis.
Although rapid and adequate administration of fluid is largely accepted as a mainstay of resuscitation in the critically ill
patient, there is still an ongoing debate on the merits of colloids against crystalloids as first line plasma expanders. The
underlying biologic rationale calls for rapid restoration of fluid losses to maintain circulating blood volume and organ perfusion.
The ageing demographic in developing countries provides an unprecedented challenge for practitioners of Intensive Care Medicine
(ICM). Over 10 years ago Callahan stated: “The future goal of medicine in the care of the aged should be that of improving
the quality of their lives, not seeking ways to extend their lives. In its long standing ambition to forestall death, medicine
has, in the care of the aged, reached its last frontier” [1].
The essential characteristic traits of a professional were first explored by Flexner [1] and others in the early 1900s. Researchers attempted to refine the traits of the “true” professions of law, medicine, and the clergy, and began comparing other groups of workers to these professions [2, 3]. In 1969, Etzioni [4] labelled nursing a “semiprofession” concurrent with changes in conceptualization of the nature of professions by others [5–6]. However, contemporary opinion is that nursing has since achieved full professional status in many countries [7]. Kimball’s comprehensive historical analysis identified that expertise, service, and associations were the three essences of a profession [8]. Nursing is now well recognized as a profession and intensive and critical care nursing is regarded as a sub specialty of the nursing profession.
Hospitals, clinics, and other health buildings occupy a unique place in our sensibilities. They are safe havens for the care
and treatment of the sick, but they are also dynamic, challenging, and risky environments marked by high levels of stress
and fragmentation in the continuity of care. Complexity is manifest in patient and treatment protocols, in the interdisciplinary
coordination and hand-offs between providers, the interdependence of humans and technology, the large volumes of information
required for decision making, and the residual uncertainty associated with these decisions. It is widely acknowledged that
the physical environment has a significant impact on health and safety. However, innovation in the design of Intensive Care
Units (ICUs) has not been done with the goal of enhancing patient safety or improving the quality of care, as these aspects
were presumed to be implicit in the clinical practice of the facility.
Intensivists, the physicians that practice the art and science of intensive care medicine, have a challenging task. Our field
of action presents unique characteristics that make it distinct from most fields of medicine: we deal with a quite heterogeneous
population, with our patients presenting a wide range of ages, comorbid diseases, reasons for seeking medical care, and specific
needs for care. Moreover, the time window for our interventions is measured often in minutes rather than in days or months.
For this reason, we traditionally practice our specialty inside special places in the hospital, the so-called Intensive Care
Units (ICUs) where all the technical and human expertise are assembled together in order to optimize the science and art of
preventing, detecting, and managing patients at risk or with already-established critical illness in order to achieve the
best possible outcomes of care. This task is a complex process, carried out on a very heterogeneous patient population, and
influenced by several variables that include religious and cultural background, different structures and organizations of
the health care systems, and major differences in the baseline characteristics of the populations.
Transfusion of blood products in the critical care setting is a common practice that has been performed for many years. Since
the 19th century, when James Blundell reported the clinical application of the treatment of hemorrhage for the first time
in the Lancet [1], blood transfusion has been the cornerstone in the treatment of severe hemorrhage, not only as a means of improving oxygen
transport capacity, but also to maintain homeostasis and reduce mortality rates [1]. The 10/30 rule was the standard of care for decades [2], but the first report of this appeared in the 1940s, when Lundy et al. [3] stated that “It is a clever idea to provide blood before surgery,” referring to patients whose hemoglobin levels were between
8 and 10 g/dL. With the more restrictive use of blood transfusion since the 1980s, there have been attempts to define specific
indications for transfusion, minimal hemoglobin levels for critically ill patients, and the benefits and potential risks of
transfusion [4].
The term malaria (from the Italian mala “bad” and aria “air”) was used by the Italians to describe the cause of intermittent
fevers associated with exposure to marsh air or miasma. The word was introduced to English by Horace Walpole, who wrote in
1740 about a “horrid thing called mal’aria that comes to Rome every summer and kills one.” The term malaria, without the apostrophe,
evolved into the name of the disease only in the 20th century. Up to that point the various intermittent fevers had been called
jungle fever, marsh fever, paludal fever, or swamp fever.
Antimicrobials are pharmaceutical drugs very frequently prescribed in the intensive care unit (ICU) setting. In the last decade,
there is a growing body of evidence showing that early and appropriate use of antimicrobials has a short-term favorable impact
on the course of critically ill patients [1–4], whereas in the long-term, antimicrobials facilitate the appearance of emerging flora and changes in resistance patterns
of pathogens that form part of the hospital ecosystem [5–6]. Over the years, a number of guidelines and strategies have been proposed to improve and optimize the use of antimicrobials
in ICU patients, which have been collectively named “antibiotic policy.”
Sepsis is a common disease in intensive care medicine representing almost one third of patient admissions. Its incidence has
substantially increased over the past decades and overall mortality has declined during this period of time. It was reported
that sepsis incidence increased from 82.7 to 240.4 per 100,000 population between 1979–2000. At the same time, sepsis global
mortality decreased from 27.8 to 17.9% [1–3]. However, the absolute number of deaths significantly increased from 21.9 to 43.9 per 100,000 population. Male gender, some
chronic diseases like diabetes, immunosuppressive states, human immunodeficiency virus infections, and malignancies are factors
that increase the risk for sepsis. Some particular conditions like progressive number of organ dysfunctions, in-hospital-acquired
infections and increasing age are associated with higher risk of death [1,4]. On the other hand, septic shock mortality only diminished from 61.6 to 53.1% [5]. This slight decline in mortality observed during recent decades could be attributable to improvements in supportive care
and/or avoidance of iatrogenic complications. For example, the instrumentation of early goal resuscitation protocols not aiming
at supranormal targets for cardiac output and oxygen delivery, and the use of lung protective strategies could explain at
least in part this favorable change. Other strategies directed to treat the pathophysiological mechanisms involved in the
septic process like recombinant human-activated protein-C (rhAPC), have also contributed to improve survival. However, mortality
remains unacceptably high and further improvement in sepsis management is needed.
Intra-abdominal infections (IAIs) are defined as an inflammatory response of the peritoneum to micro-organisms and their toxins,
which results in purulent exudate in the abdominal cavity [1–5]. They have two major manifestations: generalized peritonitis and IA abscess. Peritonitis remains a potentially fatal disease
and still represents a challenge for surgeons [3]. Although greater understanding of the pathophysiology of IAIs, improvement in critical care, and timely surgical and/or
radiological intervention have reduced the mortality associated with severe peritonitis, the rate remains unacceptably high,
ranging from 3% in localized abscess to 10% in localized peritonitis, 32% in diffuse suppurative peritonitis, and 70–80% in
complicated mixed infections [1–5]. In an effort to improve the results of treatment of severe IAIs, especially of those resulting from anastomotic leakage
or perforation of the gastrointestinal tract (GIT), new surgical techniques have been introduced.
Healthcare-associated infections (HCAI) are preventable errors. In 1999 the Institute of Medicine (IOM) released its landmark
report “To err is human.” IOM estimated that as many as 100,000 patients died from medical errors in the USA, with a cost
of over $50 billion/year [1]. The improvement of the quality of healthcare is a major concern for intensive care professionals because patients in the
intensive care unit (ICU) are thought to be particularly at risk for errors due to the complexity of the patients, interdependence
of the practitioners, and dependence on team functioning. Ensuring patients’ safety during their hospital stay requires mechanisms
to determine the incidence of adverse effects. Published reports estimate that 1.7 errors per patient per day occur in the
ICU and 148,000 life-threatening errors would occur annually in teaching hospital ICUs in the USA [2].
The Confidential Enquiry into Maternal and Child Health 2003–2005 is the 7th triennial report into maternal deaths in the
UK. The anesthesia chapter from Saving Mothers’ Lives, concerning maternal mortality due to anesthesia, is the 18th in a series
of reports within the Confidential Enquires into Maternal and Child Health and reviews the causes of maternal deaths in the
UK making recommendations for improvements in care [1].
Damage control surgery is considered by many surgeons as one of the most significant advances in the last 2 decades in the
care of trauma or other surgical patients with severe hemorrhage, which cannot easily be controlled by other techniques. In
the recent wars in Iraq and Afghanistan this approach has been used extensively and has been credited with saving many lives
[1]. The present chapter reviews the history, indications, techniques, controversies, complications, and outcomes for damage
control procedures.
Ventricular fibrillation (VF) remains the primary rhythm in many instances of sudden cardiac death, and defibrillation by
electrical counter-shock represents the treatment of choice for this otherwise lethal arrhythmia. There is no doubt that the
duration of VF remains one of the principal determinants for the likelihood of successful defibrillation. When the interval
between the estimated onset of VF and the delivery of the first shock is less than 5 min, there is evidence that an immediate
electrical shock would be successful [1]. When the duration of untreated VF exceeds 5 min, however, both human and animal studies demonstrate that initial CPR, with
chest compression, prior to delivery of a defibrillation attempt, improves the likelihood of restoration of spontaneous circulation
(ROSC) [2, 3].
Acute lung injury (ALI) and acute respiratory distress syndrome (ARDS) are clinical syndromes characterized by acute onset
of severe hypoxemia and diffuse bilateral pulmonary infiltrates in the absence of clinical evidence of left heart failure.
The mainstay of treatment is supportive care with an emphasis on the delivery of mechanical ventilation. Often these syndromes
are a part of a systemic critical illness, such as severe sepsis, polytrauma, or multiple organ failure with injury to the
lung, either directly or indirectly. Increasingly, recognition of the genetic predisposition to lung injury has enhanced our
understanding about these syndromes. Though therapeutic options are limited, evidence from prospective randomized trials over
the last decade has provided insights into mechanical ventilation and fluid management strategies for these patients, which
have improved mortality and decreased ventilator days.
Plasmodium falciparum is a protozoan parasite of human erythrocytes that causes the most severe form of malaria. Severe P. falciparum infection is associated with endothelial activation and permeability, which are important determinants of the outcome of the infection. How endothelial cells become activated is not fully understood, particularly with regard to the effects of parasite subcomponents. We demonstrated that P. falciparum histones extracted from merozoites (HeH) directly stimulated the production of IL-8 and other inflammatory mediators by primary human dermal microvascular endothelial cells through a signaling pathway that involves Src family kinases and p38 MAPK. The stimulatory effect of HeH and recombinant P. falciparum H3 (PfH3) was abrogated by histone-specific antibodies. The release of nuclear contents on rupture of infected erythrocytes was captured by live cell imaging and confirmed by detecting nucleosomes in the supernatants of parasite cultures. HeH and recombinant parasite histones also induced endothelial permeability through a charge-dependent mechanism that resulted in disruption of junctional protein expression and cell death. Recombinant human activated protein C cleaved HeH and PfH3 and abrogated their proinflammatory effects. Circulating nucleosomes of both human and parasite origin were detected in the plasma of patients with falciparum malaria and correlated positively with disease severity. These results support a pathogenic role for both host- and pathogen-derived histones in P. falciparum-caused malaria.
We report the case of a 55-year-old male European who became septic after he returned from a four-week holiday to Uganda. Soon after, he was diagnosed with severe falciparum malaria and developed multi-organ failure. Due to the worsening condition of the patient, drotrecogin alfa (activated) was started, soon after which the patient's condition significantly improved. He returned home on day 36 after admission, without neurologic sequelae.
Looking at those few cases of severe forms of malaria where drotrecogin alfa (activated) was successfully used, it should at least be considered for administration in patients with severe falciparum malaria with disseminated intravascular coagulation and cerebral involvement who do not respond to or deteriorate during standard treatment.
Travelers returning to the United States from malaria-endemic areas are at increased risk of a potentially fatal infection from Plasmodium falciparum, which requires prompt and aggressive treatment.
Described is a case of a 7-year-old boy who was infected by P. falciparum while in Africa and developed features of severe infection, including hyperparasitemia, altered neurologic status, and malarial hepatitis.
A single automated erythrocytapheresis procedure reduced parasitemia from 14% to less than 1%. Along with intravenous quinidine, this reduced parasite level was maintained throughout the hospitalization and the patient recovered.
Exchange transfusion (ET) is an effective adjunct therapy to reduce the parasite load in cases of severe P. falciparum malaria. When performed in certain defined settings, the benefits can outweigh the risks of the procedure. Discussed are the medical and technical considerations on the use of adjunctive ET for severe P. falciparum infection and a review of the literature of the use of adjunct ET in the treatment of severe P. falciparum malaria.
We report a case of Strongyloides stercoralis hyperinfection syndrome in a renal transplant recipient complicated by septic shock, acute respiratory distress syndrome, and Klebsiella pneumoniae superinfection. The patient was treated successfully with drotrecogin alfa (activated), parenteral ivermectin, albendazole, and piperacillin/tazobactam. This outcome suggests that drotrecogin alfa (activated) may be useful therapy for transplant recipients who develop severe sepsis or septic shock secondary to potentially lethal opportunistic infections.
Plasmodium falciparum infection is often associated with a procoagulant state. Recent identification of tissue factor in the brain endothelium of patients who have died from cerebral malaria casts new light on our understanding of the coagulation disorder found in P. falciparum infection. It has also been revealed that parasitized red blood cells support the assembly of multimolecular coagulation complexes. Tissue factor expression by the endothelium and amplification of the coagulation cascade by parasitized red blood cells and/or activated platelets (particularly at sequestration sites) have crucial roles in mounting and sustaining a coagulation-inflammation cycle which contributes to organ dysfunction and coma in falciparum malaria.
Activated protein C (APC) is derived from its precursor, protein C (PC). Originally thought to be synthesised exclusively by the liver, recent reports have shown that PC is also produced by endothelial cells, smooth muscle cells, keratinocytes and some leukocytes.
To provide an update on the emerging therapeutic effects of APC.
APC functions as an anticoagulant with cytoprotective, anti-inflammatory and antiapoptotic properties. In vitro and preclinical data have revealed that APC exerts its protective effects via an intriguing mechanism requiring endothelial protein C receptor and protease activated receptor-1. Approved as a therapeutic agent for severe sepsis, APC is emerging as a potential treatment for a number of autoimmune and inflammatory diseases including spinal cord injury, asthma, chronic wounds and possibly rheumatoid arthritis. The future therapeutic uses of APC look very promising.
Drotrecogin alfa (activated), or recombinant human activated protein C, has antithrombotic, antiinflammatory, and profibrinolytic properties. In a previous study, drotrecogin alfa activated produced dose-dependent reductions in the levels of markers of coagulation and inflammation in patients with severe sepsis. In this phase 3 trial, we assessed whether treatment with drotrecogin alfa activated reduced the rate of death from any cause among patients with severe sepsis.
We conducted a randomized, double-blind, placebo-controlled, multicenter trial. Patients with systemic inflammation and organ failure due to acute infection were enrolled and assigned to receive an intravenous infusion of either placebo or drotrecogin alfa activated (24 microg per kilogram of body weight per hour) for a total duration of 96 hours. The prospectively defined primary end point was death from any cause and was assessed 28 days after the start of the infusion. Patients were monitored for adverse events; changes in vital signs, laboratory variables, and the results of microbiologic cultures; and the development of neutralizing antibodies against activated protein C.
A total of 1690 randomized patients were treated (840 in the placebo group and 850 in the drotrecogin alfa activated group). The mortality rate was 30.8 percent in the placebo group and 24.7 percent in the drotrecogin alfa activated group. On the basis of the prospectively defined primary analysis, treatment with drotrecogin alfa activated was associated with a reduction in the relative risk of death of 19.4 percent (95 percent confidence interval, 6.6 to 30.5) and an absolute reduction in the risk of death of 6.1 percent (P=0.005). The incidence of serious bleeding was higher in the drotrecogin alfa activated group than in the placebo group (3.5 percent vs. 2.0 percent, P=0.06).
Treatment with drotrecogin alfa activated significantly reduces mortality in patients with severe sepsis and may be associated with an increased risk of bleeding.
The efficacy of exchange transfusion as an adjunct treatment for severe falciparum malaria is controversial. No sufficiently
powered, randomized, controlled study has been reported. We analyzed 8 studies that compared survival rates associated with
adjunct exchange transfusion with those associated with antimalarial chemotherapy alone. Exchange transfusion was not associated
with a higher survival rate than was antimalarial chemotherapy alone (odds ratio [OR], 1.2; 95% confidence interval [CI],
0.7–2.1). However, patients who received transfusions had higher levels of parasitemia and more-severe malaria. Sensitivity
analysis found that survival rates were higher among patients with partial immunity to malaria (OR, 0.5; 95% CI, 0.2–1.2)
than they were among patients with no immunity (OR, 2.1; 95% CI, 0.9–4.8; P = .007). Exchange transfusion does not appear to increase the survival rate; however, there were significant problems with
the comparability of treatment groups in the studies reviewed, and a randomized controlled trial is necessary to determine
whether exchange transfusion is beneficial.
Little is known about severe imported malaria in nonendemic industrialized countries. The purpose of this retrospective study was to describe the clinical spectrum of severe imported malaria in adults and to determine factors that were present at admission and were associated with in-intensive care unit mortality. This retrospective study evaluated the 188 patients who were admitted to our intensive care unit in 1988-1999 with severe and/or complicated imported malaria. Among them, 93 had strictly defined severe malaria, and 95 had less severe malaria. The mean age was 38 years, 51% of patients were nonimmune whites, 94% acquired Plasmodium falciparum in sub-Saharan Africa, and 96% had taken inadequate antimalarial chemoprophylaxis. Mortality was 11% (10 patients) in the severe malaria group, whereas no patients died in the less severe malaria group (p = 0.002). In the bivariable analysis, the main factors associated with death in the severe malaria group were the Simplified Acute Physiology Score, shock, acidosis, coma, pulmonary edema (p < 0.001 for each), and coagulation disorders (p = 0.002). Bacterial coinfection is not infrequent and may contribute to death. Severe imported malaria remains a major threat to travelers. In our population, the most relevant World Health Organization major defining criteria were coma, shock, pulmonary edema, and acidosis.
To compare the efficacy of exchange transfusion as the adjunct to quinine treatment (21 patients) with quinine therapy alone (29 patients).
A retrospective study of 50 patients with severe falciparum malaria was conducted at Chumphorn Hospital, Southern Thailand.
Clinical characteristics in both treatment groups were not significantly different although in the exchange transfusion group, the admission geometric mean parasitaemia (18 (5%), and the proportion of patients with more than 10% parasitaemia was higher (76%, P = 0.03) than in the group who received quinine alone (10 +/- 4%; 38%, P = 0.1). The mortality rate of patients who received exchange transfusion was 48%; that of the remainder, 69%. (P = 0.3). ARDS (P = 0.01) and oliguric renal failure (P = 0.04) were significant risk factors for death in these patients.
Exchange transfusion was safe and well tolerated. Results of our study revealed a 20% reduction in mortality when exchange transfusion was used as an adjunct to quinine treatment. It should therefore be considered in patients with severe falciparum malaria when possible.
The mechanisms involved in the activation of the coagulation cascade in severe falciparum malaria were studied in 22 adult patients (19 male, three female) aged 18-45 (mean +/- SD 31 +/- 11) years. Of these, nine had multiple vital organ dysfunction, and bleeding occurred in four patients, two of whom died. During acute illness the reduction in plasma antithrombin III (AT III) concentrations and elevation in thrombin-AT III complexes were associated with significant reductions in factor XII and prekallikrein activities, and an increase in the C1 inhibitor antigen/activity ratio. Serial plasminogen activity remained within the normal range in all patients while protein C activity was significantly reduced. All patients had markedly elevated plasma polymorphonuclear leucocyte elastase (PMN-elastase) levels with mild depletion of alpha-2 macroglobulin but normal concentrations of alpha-1 antitrypsin. There was no correlation between PMN-elastase concentrations and any of the coagulation parameters or concentrations of proteinase inhibitors. These results suggest that the intrinsic pathway of the clotting cascade is activated in severe malaria. This may cause activation of the complement system and release of bradykinin and PMN-elastase and could contribute to the pathogenesis of severe malaria.
Management of severe malaria is an increasing problem worldwide. This paper reviews the pathophysiology and management documenting two years’ experience of admissions of severe malaria to an ICU in a non-endemic area.
Clinical and laboratory features of severe malaria were analysed for predictors of mortality. Twenty-eight patients had clinical or laboratory features compatible with the WHO criteria for severe malaria and, despite treatment with intravenous quinine and supportive ICU care, mortality was 28.5% (8/28).
The three pregnant patients died with 100% foetal mortality and the four paediatric patients survived. Of the non-survivors, 8/8 developed ARDS (defined by worst ALI score >2.5), 7/8 developed shock requiring inotropic support and 7/8 developed acute renal failure requiring CVVHD.
Admission haemoglobin, platelet count, parasite count, and lowest Glasgow Coma Score in the first 24 hours were shown not to be predictors of mortality.
To study adult patients with severe falciparum malaria who developed shock.
Retrospective study from 1987 to 1993.
Medical intensive care unit in a university hospital.
14 patients admitted with severe falciparum malaria who developed shock. All received intravenous quinine.
The mean Simplified Acute Physiology Score II was 59.5 +/- 7.1; 2.6 +/- 0.4 criteria defining severe disease were present on admission in 12 patients; and initial parasitemia was 21 +/- 6%. Twelve patients received inotropic drugs. Pulmonary artery catheterization showed the following results in 7 patients: mean arterial pressure 57 +/- 4 mmHg; pulmonary artery occlusion pressure 11 +/- 1 mmHg; cardiac index 5.5 +/- 0.91.min-1.m-2, and systemic vascular resistance index 783 +/- 122 dyne.s.cm-5.m-2. Seven patients had evidence of bacterial infection at the time of shock. Of the 7 deaths (50%), 5 were due to shock, with documented bacterial infection in all patients and persistent parasitemia in 4.
Shock complicating severe falciparum malaria in adults is associated with peripheral vasodilation and carries a poor prognosis. In falciparum malaria with shock, bacterial coinfection should be suspected immediately and treated empirically with broad-spectrum antibiotics. Nevertheless, Plasmodium falciparum may contribute directly or indirectly to the onset of shock.
To review the clinical profiles and therapies instituted for patients with severe malaria admitted to an ICU.
Retrospective study.
Internal ICU of a tertiary care centre.
Between January, 1992, and February, 1999, 104 patients with malaria were admitted to the General Hospital of Vienna. Sixty-nine patients suffered from Plasmodium falciparum malaria (66%), seven of these were admitted to the ICU.
Seven patients were admitted to the ICU, of whom three died (4% in hospital case-fatality rate). Four patients required mechanical ventilation because of respiratory insufficiency and adult respiratory distress syndrome (ARDS), of whom three died. Three patients were treated with inhaled nitric oxide (NO) and kinetic therapy; one patient required extracorporeal veno-venous oxygenation. All patients who died required haemofiltration because of acute renal failure.
As P. falciparum is a potentially life-threatening disease, reliable criteria for ICU admission should be defined and risk factors identified. Early ICU monitoring should be attempted, especially under the following conditions: (1) lack of clinical response to anti-malarial treatment within 48 h and/or (2) any signs of neurological disturbance (hypoglycaemia excluded). Prospective multicentre trials and guidelines for supportive intensive care are urgently needed.
Hypoglycaemia and lactic acidosis are potentially life-threatening, poorly understood sequelae of Plasmodium falciparum infections. We investigated relationships between clinical status, treatment, and glucose and lactate kinetics during management of falciparum malaria in 14 Vietnamese adults. Nine had severe malaria, of whom 4 were administered quinine (Group 1a) and 5 artesunate (Group 1b). Five uncomplicated cases received artesunate (Group 2). Glucose and lactate turnover were studied on 3 occasions: (i) immediately after initial antimalarial treatment, (ii) at parasite clearance a median of 3 days later, and (iii) at discharge from hospital a median of 9 days post-admission. Steady-state glucose and lactate kinetics were derived from plasma isotopic enrichment during a primed-continuous infusion of D-[6,6-D2]glucose and a parallel infusion of L-[1-13C]lactate. Group 1a patients had the lowest plasma glucose concentrations in the admission study (median [range] 3.9 [3.6-5.1] vs 6.3 [4.9-7.1] and 4.5 [4.3-5.5] mmol/L in Groups 1b and 2 respectively; P < 0.05 vs Group 1b), but glucose production rates and serum insulin concentrations that were similar to those in the other groups (P > 0.17). This was also the case at parasite clearance and suggested an inappropriate beta cell response. Group 1a patients had the highest admission lactate production (60 [36-77] vs 26 [21-47] and 22 [4-31] mumol/kg.min in Group 1b and 2 respectively; P < 0.05 vs Group 2). Amongst the 9 severe cases, there was an inverse association between plasma glucose and lactate production at admission and parasite clearance (P < 0.05), but no correlation between admission lactate production and serum bicarbonate (P = 0.73). The present data confirm previous studies showing that quinine depresses plasma glucose through stimulation of insulin secretion. It is hypothesized that the low plasma glucose activates Na+,K(+)-ATPase through increased plasma catecholamine concentrations, leading to accelerated glycolysis and increased lactate production in well-oxygenated tissues. In some severely ill patients with falciparum malaria, a raised plasma lactate on its own may, therefore, be an unreliable index of a developing acidosis.
To explore the relationship between measures of baseline disease severity and survival time in patients with severe sepsis.
A retrospective evaluation of the placebo group from a large placebo-controlled phase III clinical trial (PROWESS) comprising a total of 840 patients with severe sepsis from 164 medical centers.
Data collected included baseline demographics and disease severity measurements, baseline protein C and interleukin-6 levels, 28-day and in-hospital survival rates, and cause of death to 28 days. The survival curve for the placebo patients can be divided into three segments during which the rate of death seemed to be different: the rapid alpha phase (day 0 to day 5), the beta phase (day 6 through day 15), and the gamma phase (day 16 to day 28). The risk of death during each phase was statistically significantly different. More patients died of refractory shock during the alpha phase than in the beta and gamma phases, whereas more patients died of respiratory failure during the beta and gamma phases than during the alpha phase. Multiple organ failure was a frequent cause of death during all phases. Protein C levels at the start of each time interval were highly predictive of outcome within that phase, with continued protein C deficiency being associated with mortality. Patients who died during either the alpha or beta phases had higher interleukin-6 levels at baseline than those who died later or who eventually survived.
The rate and cause of death for patients with severe sepsis differs during the 28-day postdiagnosis period. Severe protein C deficiency (<40% of the level of protein C in pooled normal human plasma) and high interleukin-6 levels were associated with early death that resulted predominantly from refractory shock and multiple organ dysfunction.
World Health Organization Management of Severe Malaria. A Practical Handbook Protection Agency
World Health Organization. Management of Severe Malaria.
A Practical Handbook, 2nd edn. Geneva: WHO, 2000.
Protection Agency. http://www.hpa.org.uk.
AE Drotrecogin alfa (activated) in malaria Anaesthesia
- B J L Kendrick
B. J. L. Kendrick et al. AE Drotrecogin alfa (activated) in malaria
Anaesthesia, 2006, 61, pages 899–902