32

REVIEW

ABSTRACT

Blood pressure is crucial for the tissue perfusion, oxygenation and elimination of metabolites in normal tissue. In septic patients it may be altered by several mechanisms. Endothelial lesions and impaired vasoregulation resulting from bacteriemia may produce vasodilatation, hypotension, tissue hypoxia and decrease in the blood velocity. These events may favour disseminated intravas-cular coagulation in septic patients, and thus pronounce perfu-sion misdistribution. Since hypotension is commonly treated by vasoactive drugs to increase vascular tone toward normal values, more pronounced peripheral tissue ischemia may result. During the process of blood pressure regulation in septic patients a diver-sity of physiological parameters should be encountered, i.e. age, body weight, core temperature, overall patients’ cardiovascular performance, anemia, and protein status. In a healthy, adult per-son, in the absence of other causes of hypotension systolic blood pressure of > 90 mmHg or mean arterial pressure ≥ 70 mmHg should maintain adequate tissue perfusion. Together with specific antibiotics, therapeutic procedures like haemodilution, use of va-soconstrictors, vasopressin and its analogue terlipressin, corticos-teroids are currently used to improve outcome of hypotensive sep-tic patients. Numerous studies were undertaken to point the values of the biochemical tests suggesting a need for prompt interven-tion. The arterial lactate, cortisol response, TNF, interleukin (IL) 6, IL-12p70 and IL-12p40 production, together with submucosal (gastric intramucosal or sublingual) CO2 values were proven as in-dicative. These may suggest whether microcirculatory impairment is reversible or not, and which therapeutic maneuver should be appropriate.

Key words: sepsis, shock, blood pressure, vasoconstrictor agents

Microcirculation impairment and blood pressure in sepsis

Slavica Kvolik1,2, Ines Drenjančević-Perić2, Ines Takač1, Marko Jukić3, Domagoj Drenjančević2,4

1Department of Anaesthesiology and ICU, Clinical Hospital Osijek, 2School of Medicine, University Josip Juraj Strossmayer Osijek, 3Department of Anaesthesia and ICU, KBC Split, 4Department of Clinical Microbiology, Clinical Hospital Osijek; Croatia

Corresponding author:

Slavica Kvolik

Department of Anaesthesiology and ICU,

Clinical Hospital Osijek,

J. Huttlera 4, 31000 Osijek; Croatia

E-mail: skvolik@mefos.hr

Phone:. +385 31 206 444

Original submission:

18 September 2008;

Revised submission:

11 November 2008;

Accepted:

24 November 2008.

Med Glas 2009; 6(1): 32-41

33

Kvolik et al Blood pressure in sepsis

INTRODUCTION

Sepsis is characterized by the reduction in the peripheral vascular tone on both the arterial and venous sides of the circulation and impaired oxygen utilization resulting in the elevated lactate levels, and varying degree of organ dysfunction. Early ‘warm’ phase is recognized by vasodilata-tion, acidosis, fever, tachycardia, tachypnoea, respiratory alkalosis and an increased cardiac output with warm, dry peripheries (1). Advanced sepsis presents with the signs of organ failure: myocardial contractile dysfunction with low cardiac output, progressive acidosis, respiratory failure, clammy peripherally shut down, and with progressive neurologic disorder. Late or ‘cold’ sepsis is characterized by vascular hypo-reactiv-ity, multiple organ dysfunctions with profound acidosis and frequently death (1).

Microvascular impairment and blood pres-sure (BP) regulation are crucial for the outcome of septic patients, being in the same time a marker of the disease severity and progression, and predic-tor of the treatment efficiency. This paper presents a diagnostic and therapeutic approach to the BP regulation in the severe sepsis and septic shock.

PATHOPHYSIOLOGY

Three integrated components of severe sepsis are: infection with systemic activation of inflam-mation, activation of coagulation and impairment of fibrinolysis (2).

During the development of sepsis, various proinflammatory cytokines are released, such as endotoxin-induced tumour necrosis factor (TNF), interleukin-1 (IL-1), and interleukin-6 (IL-6). These proinflammatory cytokines induce en-dothelial injury and vascular bed-specific chang-es (2). The endothelial damage and increased thrombogenicity are linked to the development of the clinical signs of sepsis (2, 3). Inflamma-tory changes trigger the extrinsic coagulation pathway, which is mostly subclinical, but can be observed in the commonly measured haemo-static parameters (4). The most deleterious form

of the haemostatic system activation in sepsis is the disseminated intravascular coagulation. It is characterized by coagulation activation on the activated endothelium and subsequent bleeding, as a resultant of coagulation factors consumption (4). In the sepsis normal fibrinolytic response is suppressed by fall in plasminogen levels while antiplasmin levels remains normal and thrombin-antithrombin (TAT) complexes increases (4). Typically, tissue factor expression is increased in a subset of endothelial cells and plasminogen activator inhibitor-1 is released and impairs fibri-nolysis (2, 3). Fibrinolysis is further impaired by the generation of increased amounts of thrombin-activatable fibrinolysis inhibitor (TAFI) (4). Although plasminogen/antiplasmin ratio and plasminogen activator inhibitor-1 (PAI-1) levels remain abnormal in non-surviving patients, they tend to normalize in survivors (4).

The endothelial cell is the central point of in-teractions between the inflammatory events and disturbed hemostasis in patients with severe sep-sis (3, 4, 5). Endothelial cell injury or death can shift the cell’s phenotype to prothrombotic and induce sequestration of inflammatory cells and platelets in the damaged vessels. The resulting microvascular flow obstruction produces acute organ dysfunction with hypoperfusion/ischemia and can ultimately lead to dead (4).

SEPSIS RESULTS IN DOWN-REGULATION OF ADRENERGIC RECEPTORS

Recent study investigating the role of adrener-gic system in sepsis showed that the pressor effect of norepinephrine was markedly diminishing dur-ing endotoxemia (5). Endotoxemia causes a sys-temic down-regulation of alpha1-receptors on the level of gene expression and suggest that this effect is likely mediated by proinflammatory cytokines in a synergistic but nitric oxide-independent fashion. This down-regulation of alpha1-adrenergic recep-tors contributes to the attenuated BP response to norepinephrine and, therefore, to circulatory fail-ure in septic patients (5). Furthermore, study by Bernardin et al demonstrated that patients with

Medicinski Glasnik, Volumen 6, Number 1, February 2009

34

severe sepsis or septic shock had postreceptor de-fects of the beta-adrenergic signal transduction. This finding suggests a heterologous desensitiza-tion of adenylate cyclase stimulation (6). Also, the serum of patients with sepsis contains soluble de-pressant substances that inhibited adenylyl cyclase activation by beta-adrenergic agonists. Hyperacti-vation of the Gi pathway of adenylyl cyclase was mainly responsible for the altered transmembrane beta-adrenergic signalling (7). An impairment of beta-adrenergic signaling was observed in healthy peripheral blood mononuclear cells exposed to serum from patients with septic shock due to the involvement of the inhibitory pathway of adeny-lyl cyclase stimulation (7). These findings could explain sometimes ineffective therapy with adren-ergic agonists in septic patients (8, 9).

BIOMARKERS OF THE OUTCOME IN SEPTIC PATIENTS

Several biochemical markers like blood lactate levels, C-reactive protein (CRP), TNF, procalcitonin and lipopolysaccharide binding protein may be used as biomarkers of the sepsis severity and predictors of outcome (9, 10). Cur-rent recommendations do not support routine as-sessment of any laboratory markers during the sepsis treatment as indicators of disease progress and treatment efficiency, except of blood gas and lactate values. Although pH and blood lactate concentration may lack precision as a measure of tissue metabolic status, pH < 7.14 and elevated lactate levels (≥ 4 mmol L-1) in the sepsis support aggressive resuscitation (8).

HEMODYNAMIC MEASUREMENTS IN THE SEPTIC SHOCK

Hemodynamic measurements are accepted as gold standards for monitoring in septic patients. The pulmonary artery flotation catheter is current-ly replaced with less invasive monitoring methods, such as PICCO (pulse contour cardiac output), LIDCO (lithium dilution cardiac output), and tran-scutaneous oxygen pressure monitoring (1, 8, 9).

Mixed venous oxygen saturation is a useful sur-rogate for the cardiac index (CI) as a target for he-modynamic therapy in adult population (8. 9). In cases in which the insertion of a pulmonary-artery catheter is impractical, venous oxygen saturation can be measured in the central circulation (9).

Measurement of cardiac output and oxygen consumption are reliable predictors of the sep-sis outcome in children with septic shock (11). American College of Critical Care Medicine has provided clinical guidelines for hemodynamic support of neonates and children with septic shock, and identified the critical values of hemo-dynamic parameters that were associated with improved survival. CI between 3.3 and 6.0 L/min/m2 and oxygen consumption >200 mL/min/m2 are identified as predictive factors. With he-moglobin concentration of 10 g dL-1 and 100% arterial oxygen saturation, the CI of >3.3 L/min/m2 correlates to a mixed venous oxygen satura-tion of >70% (11).

A SCORING OF MICROCIRCULATION IN THE SEPSIS

Standard non-invasive and invasive BP meas-urements were unable to evaluate the dynamics of microcirculation changes in the septic patients (12). In the recent years new devices have been introduced to study end organ perfusion in septic patients. Gastric tonometry alone or in the combi-nation with laser Doppler flowmetry is currently the most widely used technique (12). The role of the diagnostic techniques that allow the microcir-culation to be visualized directly is emerging. The orthogonal polarization spectral (OPS) and the sidestream dark field imaging devices provide high contrast images of capillaries and venules contain-ing red blood cells. Different microcirculation scoring systems were reported, aimed to compare the results obtained using such devices, and to pre-dict the outcome (12). De Backer and colleagues have proposed that scoring of the microcirculation should include: an index of vascular density, total and perfused vessel density, the perfusion index (proportion of perfused vessels), microcirculatory

35

flow index (MFI) and heterogeneity index (13). The persistent microvascular alterations observed using such imaging devices were more severe in nonsur-vivors than in survivors, and were associated with the development of multiple organ failure (MOF) and death. They typically include decreased capil-lary density, and decreased perfusion of capillar-ies. The substantial heterogeneity in microvascular perfusion can be observed in advanced and late sepsis with microinfarctions and/or bleeding areas (Figure 1) (13). Despite similar hemodynamic and oxygenation profiles and use of vasopressors at the end of shock, patients dying after the resolution of shock in MOF had a lower percentage of perfused small vessels than survivors (57.4 vs. 79.3 %). Al-though both survivors and nonsurvivors had initial decrease in the small vessels perfusion registered at the sepsis onset, microcirculatory alterations im-prove rapidly in survivors but not in patients dying with MOF (10).

Using these devices, several microcirculation impairments in sepsis may be reported earlier, i.e. decrease in the gut mucosal circulation and skin hypoperfusion, arguing for specific therapies or for the discontinuation of harmful ones (14, 15). However, such devices are not widely accepted until now, and the usefulness of data obtained by these methods in the clinical decision-making is still limited (16).

Several outcome prediction systems are cur-rently used to evaluate organ dysfunction in the intensive care unit, i.e. Sequential Organ Fail-ure Assessment (SOFA) score, Multiple Organ Dysfunction Score (MODS) and acute physiol-

ogy and chronic health evaluation (APACHE II). They may reliable predict outcome, but are not appropriate during the decision making process in the critical septic patients requiring rapid re-suscitation (17).

CRITICAL BLOOD PRESSURE VALUES IN SEPTIC PATIENTS

The surviving Sepsis Campaign experts de-fined sepsis induced hypotension as a systolic blood pressure (SBP) < 90 mm Hg or mean arte-rial pressure (MAP) < 70 mm Hg or a SBP de-crease > 40 mm Hg or < 2 SD below normal for age in the absence of other causes of hypotension. Sepsis induced hypotension persisting despite adequate fluid resuscitation is considered as sep-tic shock (8). As a consequence of hypotension, a persistent microvascular perfusion derangement may result in the organ failure and death (8).

Early hemodynamic interventions in the sep-tic shock aimed at rapid normalization of arterial pressure, oxygen delivery and oxygen consump-tion are key factors adding to in-hospital mortal-ity. The severity and duration of hypotension are associated with a poor outcome (9).

Target values of early goal directed therapy (EGDT) are confirmed in the Surviving Sepsis Campaign guidelines for the management of se-vere sepsis and septic shock (8, 9). The goals of initial resuscitation of sepsis-induced hypoper-fusion should include all of the following as one part of a treatment protocol: central venous pres-sure (CVP ) 8-12 mm Hg, systolic blood pressure

Figure 1. The evolution and outcome of circulation changes on the left knee skin in five-month old child who survived severe sepsis and septic shock. A) third day after the onset of sepsis with hypotension: areas of hypoperfusion presenting as violet-blue irregularly shaped skin changes with central ischemia and marginal bleeding; B) one month later: a demarcation of deep black necrotic areas and formation of scars in the more superficially hypoperfused areas; C) two months later: a retraction of residual hyperpigmented scars in the areas of deep necroses. (I. Takač, 2006; with parents’ permission).

Kvolik et al Blood pressure in sepsis

Medicinski Glasnik, Volumen 6, Number 1, February 2009

36

≥90 mm Hg or MAP ≥65 mm Hg, and central venous (superior vena cava) or mixed venous ox-ygen saturation ≥70% or ≥ 65%, and urine output ≥0.5 ml kg-1hr-1 (8).

Blood pressure dynamic reflects vascular tone and correlates with the tissue oxygen de-livery. It may parallel with biochemical mark-ers, but in some clinical situations it is the first sign of organ function deterioration in septic pa-tients, especially in the patients suffering from brain trauma, polytrauma or in children (11). Once the antibiotic therapy has been initiated, the hemodynamic optimization strategies tar-geting adjustments of cardiac preload, afterload and contractility to balance oxygen delivery with oxygen demand may substantially improve outcome (9). A significant decrease in biomarker levels was observed as early as 3 hrs for IL-1ra and ICAM-1, 6 hrs for TNF-α and caspase-3, and 12 hrs for IL-8 as a result of EGDT (17). A vascular hyporeactivity to hemodynamic sup-portive therapy is usually a marker of poor out-come (19).

Several mechanisms have been evoked to explain why early (but not late) hemodynamic-oriented interventions could be effective. One is that irreversible organ damage is already present when late interventions are applied, and alterna-tive explanation may be that early interventions can attenuate the proinflammatory response, breaking a vicious cycle that could result in organ failure and death (9, 20).

The critical blood pressure value that should maintain tissue perfusion highly depends upon the patient’s physiologic performance and co-morbidities, assuring thus critical oxygen and glucose delivery (21). Comorbidities are signifi-cant factors for predicting the treatment failure in sepsis. A history of pre-existing coronary ar-tery disease and surgical emergencies in septic patients may be associated with poor outcome (21). Patients with history of severe hypertension may furthermore require higher MAP or per-fusion pressure for assuring tissue perfusion and oxygenation, whereas lower MAP may be suffi-cient for previously healthy young person (22).

In the haemodynamically compromised patients the values of perfusion pressure may be more ap-propriate for the circulation evaluation (23). Per-fusion pressure is a difference between MAP and CVP (MAP-CVP). In newborns and children, lower age adjusted pressure thresholds should be considered (11), as shown on Table 1.

DRUGS IN THE BLOOD PRESSURE REGULATION IN SEPTIC PATIENTS

Antibiotic therapy

A type of bacteria and it’s treatment is im-portant for both BP and survival in the sepsis and septic shock. A study of Kumar in the cohort of 2,154 septic shock patients confirmed a strong relationship between the delay in antimicrobial therapy after the onset of recurrent or persistent hypotension and in-hospital mortality (24). An early administration of an antimicrobial effective for causative pathogens within the first hour of registered hypotension (a MAP of <65 mm Hg) was associated with a survival rate of 79.9%. Each hour of delay in antimicrobial treatment over the ensuing 6 hrs was associated with a mean decrease in survival of 7.6%. In multivariate analysis time to initiation of effective antimicrobial therapy was the single strongest predictor of the restoration of blood pressure and outcome (25).

Kumar have reported an observation that only 50% of septic patients received effective antimi-crobial therapy within 6 hrs of documented hypo-tension (24, 25). Since infections can be confirmed in almost 80% of cases, predominantly originating from respiratory system (almost entirely pneumo-nia) and gastrointestinal or intra-abdominal sites

MAP-CVP (cm H2O)

Threshold heart rates (bpm)

Term newborn 55 120-180 < 1 year 60 120-180< 2 years 65 120-160< 7 years 65 100-140< 15 year 65 90-140

Table 1. Age adjusted perfusion pressure and threshold pulse rates (Modified from: Carcillo JA, Fields AI; American College of Critical Care Medicine Task Force Committee Members. Clini-cal practice parameters for hemodynamic support of pediatric and neonatal patients in septic shock. Crit Care Med 2002; 30: 1365-1378.)

37

which together accounted for two thirds of all in-fections resulting in septic shock, this proportion is still unacceptably low. Therefore the special measures of infection identification, clinical ex-amination and early antibiotic therapy with ther-apies aimed at blood pressure optimization may significantly improve outcome (8, 24).

Volume loading

Hipovolemia is the first imbalance targeted during the initial fluid resuscitation. New recom-mendations on the sepsis treatment proposed by International Surviving Sepsis Campaign Guide-lines Committee (8) argue for the volume loading maintaining CVP at 8 mmHg, or 12 in the me-chanically ventilated patients. A fluid challenge technique is preferred, starting with at least 1000 ml of crystalloids, or 300-500 ml of colloids over 30 min. Greater amounts of fluid and more rapid administration may be given in patients with sep-sis induced tissue hypoperfusion. Fluid adminis-tration should be continued as long as the hemo-dynamic improvement continues, and reduced if CVP or pulmonary artery balloon-occluded pres-sure increases without concurrent hemodynamic and tissue perfusion improvement (8).

In the clinical praxis either natural/artificial colloids or crystalloids are used during the fluid resuscitation. Albumin solutions were proven as equally safe as crystalloids in the volume resusci-tation, and hydroxyethyl starch (HES) infusions were beneficial in inducing haemodilution in the septic shock (8, 26). HES 130/0.4 infusion was as effective patients with sepsis as in controls with-out sepsis, and may remain within the intravas-cular space even in the septic patients (26). Since meta analyses have not confirmed the superiority of each solution in the volume resuscitation, cur-rent recommendations do not suport the use of one type of fluid over another (8).

Vasopressors

Vasopressor therapy is required in the thera-peutic management of hypotension in severe sep-

tic shock (8). Norepinephrine or dopamine are first choice vasopressor agents. Norepinephrine is often favoured because of its reliable effective-ness to achieve and maintain an adequate MAP, due to vasoconstrictive effects, with little change in heart rate and minor increase in stroke volume compared with dopamine (27).

Animal studies have confirmed that the use of norepinephrine was associated with improved MAP, sustained aortic and mesenteric blood flow, and better tissue oxygenation when compared with fluid resuscitation alone, irrespective of time of administration. Furthermore, the early use of norepinephrine with volume expansion was as-sociated with a higher proportion of blood flow redistributed to the mesenteric area, lower lactate levels, and less infused volume (28).

Epinephrine, phenylephrine, or vasopressin should not be administered as the initial vaso-pressor in septic shock (8). Although there are no high quality studies favouring one catecholamine over another, some of them have confirmed epinephrine’s potential for tachycardia and dis-advantageous effects on splanchnic circulation and hyperlactemia. Epinephrine should be only used as an alternative drug in the septic shock patients poorly responsive to norepinephrine or dopamine (8).

Low doses of vasopressin may be effective in rising blood pressure in patients refractory to other vasopressors (8). Since vasopressin has quite a short half-time (6 mins), its analogue terlipressin, with a longer half-life (6 hrs), was investigated in numerous clinical trials (16, 29). The benefits and disadvantages of vasopressin or terlipressin over norepinephrine are still a matter of clinical investigations. In patients with hyper-dynamic septic shock, both norepinephrine and terlipressin effectively raised mean arterial blood pressure, cerebral perfusion pressure and a urine production (14).

A major disadvantage observed with both pure vasoconstrictors is tissue ischemia. In such patients microcirculatory monitoring i.e. OPS imaging might provide a substrate for earlier ob-

Kvolik et al Blood pressure in sepsis

Medicinski Glasnik, Volumen 6, Number 1, February 2009

38

servations of skin necrosis and a decline of gut mucosal circulation (14, 15).

The recent VASST trial comparing norepine-phrine alone to norepinephrine plus vasopressin showed no difference in outcome between two groups of septic shock patients (30). SSC guide-lines suggest that vasopressin 0.03 U min-1 may be subsequently added to norepinephrine with anticipation of an effect equivalent to norepine-phrine alone (8).

Inotropic therapy

Dobutamine infusion (up to maximum of 20 μg kg−1 min−1) is first line inotrope for patients with myocardial dysfunction as suggested by el-evated cardiac filling pressures and low cardiac output (8). It should be used during the first 6 hrs of resuscitation of severe sepsis or septic shock, if hematocrit is ≥ 30% but SCVO2 of 70% or SvO2 65% is not achieved with fluid resuscitation to the CVP target. In the septic patients who re-main hypotensive after fluid resuscitation, a treat-ment with a combined inotrope/vasopressor such as norepinephrine or dopamine is recommended if cardiac output is not measured. When cardiac output in addition to blood pressure is monitored, a vasopressor such as norepinephrine may be ad-ministered separately to target desired levels of MAP and cardiac output (8).

Adequate fluid resuscitation is a fundamental therapy in patients with septic shock, and should ideally be achieved before vasopressors and ino-tropes are used. However, using vasopressors as an emergency measure in patients with severe shock is frequently necessary, even when hypo-volemia has not yet been resolved (8, 24).

Vasopressors should be administered through a central venous catheter. Arterial line has to be placed as soon as possible to allow continuous analysis and reproducible measurement of AP. Using these catheters, decisions regarding ther-apy can be based on immediate and reproducible blood pressure information (8).

Corticosteroids

Corticosteroids were proposed for the treat-ment of sepsis as early as 1940. A rationale is an adrenal insufficiency which is present in about half of patients with septic shock and is associ-ated with higher rates of refractory hypotension and mortality (31).

A moderate dose of glucocorticoids appears to be beneficial in the patients with relative adre-nal insufficiency (nonresponders to the cortico-tropin test) (32).

Intravenous corticosteroids are currently recommended only for hypotensive adult sep-tic shock patients who are poorly responsive to adequate fluid resuscitation and vasopressors. In such patients high doses of corticosteroids are not beneficial. A replacement dose of hydrocortisone, about 300 mg daily for 5-7days, should be used instead of it (31). Hydrocortisone is preferred to dexamethasone in the treatment of septic shock, although it was not confirmed as effective in all patients. In the patients with hydrocortisone has-tened reversal of shock it increases arterial pres-sure and improves 28-day mortality (33). A meta-analysis of all available clinical controlled studies showed a reduction in 28 days and in-hospital all-cause mortality with glucocorticoids (31, 33).

Other supportive therapies in the sepsis

Blood products should be given to target he-moglobin of 70.0–90.0 g L-1, or ≥ 100 in patients with myocardial ischemia, severe hypoxemia, acute hemorrhage, cyanotic heart disease or lac-tic acidosis (8, 27).

A bicarbonate therapy is not recommended for the purpose of improving hemodynamics or reducing vasopressor requirements when treating hypoperfusion-induced lactic acidemia with pH ≥ 7.15 or high blood lactate concentration (8).

To counterbalance activated coagulation cas-cade in the septic patients, several haemostatic agents (ATIII, TFPI, heparin) were investigated by means of improving outcome (8). Among

39

them only a recombinant version of activated pro-tein C (rhAPC) is currently recommended in the sepsis treatment. The rhAPC treatment should be considered in adult patients with sepsis-induced organ dysfunction with clinical assessment of high risk of death (typically APACHE II ≥25 or MOF) if there are no contraindications (8). De Backer and colleagues have used an OPS imag-ing technique and confirmed that proportion of perfused capillaries increased in the rhAPC treat-ed patients with a more rapid resolution of hyper-lactatemia already at 4 hrs (from 64% to 84%, p < .01) but not in the control group treated using standard treatment (13).

Other therapies, including bacterial modula-tors (antiendotoxin, lipopoysacharide-binding pro-tein [LPB], antiCD14 monoclonal antibody), anti-cytokines (IL-1ra, anti-TNF, sTNF-r, TNFR:Fc), antiinflammatory agents (leukocyte adhesion mol-ecule inhibitors), iNOS inhibition, antioxidants, thromboxane antagonists, bradykinin receptor an-tagonists are now investigated in the population of patients with severe sepsis (34, 35). The treatment of sepsis in the immunocompromised patients rep-resents a special problem. It is very often unsuc-cessful and with lethal outcome (25).

REVERSIBILITY OF CIRCULATION CHANGES IN THE SEPTIC PATIENTS

A reversibility of hemodynamic changes in the sepsis correlates with several parameters: the

type of underlying bacteria, timing of antimicro-bial agents and with the reactivity to catecho-lamine stress. A dynamic cardiovascular response to catecholamines is well recognized marker of mortality in septic patients (19). Kumar identi-fied two critical parameters highly correlating with survival: catecholamine induced increase in the stroke volume and preserved cardiovascular reserve including preload reserve (19).

The endpoints of vasopressor therapy and other supportive therapies are adequate BP, nor-malization of the heart rate, regional and global perfusion with capillary refill of < 2 seconds, warm extremities with no differences between peripheral and central pulses, normal blood lac-tate concentrations, urine output > 1mL kg –1hr–1, and normal mental status (8). Reversal of septic shock was defined as the maintenance of a systo-lic blood pressure of at least 90 mm Hg without vasopressor support for at least 24 hours (33).

The blood pressure deregulation with pro-found hypotension is a life threatening complica-tion in the severe sepsis and septic shock. An iden-tification and early therapy of this life threatening disorder may significantly improve outcome.

ACKNOWLEDGEMENT/DISCLOSURE

Written consent was obtained from the child’s parents for publication of the Figure 1.

REFERENCES

MacKenzie IM. The haemodynamics of human 1. septic shock. Anaesthesia 2001; 56:130-44.van Deventer SJH, Buller HR, ten Cate JW, 2. Aarden LA, Hack CE, Sturk A. Experimental endotoxemia in humans: analysis of cytokine re-lease and coagulation, fibrinolytic, and comple-ment pathways. Blood 1990; 76:2520-6.

Levi M, van der Poll T, ten Cate H, van De-3. venter SJ. The cytokine-mediated imbalance be-tween coagulant and anticoagulant mechanisms in sepsis and endotoxaemia. Eur J Clin Invest. 1997;27:3-9. Kidokoro A, Iba T, Fukunaga M, Yagi Y. Altera-4. tions in coagulation and fibrinolysis during sep-sis. Shock 1996; 5:223-8.

Kvolik et al Blood pressure in sepsis

Medicinski Glasnik, Volumen 6, Number 1, February 2009

40

Bucher M, Kees F, Taeger K, Kurtz A Cytokines 5. down-regulate alpha1-adrenergic receptor expres-sion during endotoxemia. Crit Care Med 2003; 31:566-71.Bernardin G, Strosberg AD, Bernard A, Mattei 6. M, Marullo S. Beta-adrenergic receptor-depend-ent and -independent stimulation of adenylate cy-clase is impaired during severe sepsis in humans. Intensive Care Med 1998; 24:1315-22.Bernardin G, Kisoka RL, Delporte C, Robberecht 7. P, Vincent JL. Impairment of beta-adrenergic sig-naling in healthy peripheral blood mononuclear cells exposed to serum from patients with septic shock: involvement of the inhibitory pathway of adenylyl cyclase stimulation. Shock 2003; 19:108-12.Dellinger RP, Levy MM, Carlet JM, Bion J, 8. Parker MM, Jaeschke R. International Surviving Sepsis Campaign Guidelines Committee: Surviv-ing Sepsis Campaign: international guidelines for management of severe sepsis and septic shock: 2008. Crit Care Med 2008; 36:296-327.Rivers E, Nguyen B, Havstad S, Ressler J, Muz-9. zin A, Knoblich B, Peterson E, Tomlanovich M. Early Goal-Directed Therapy Collaborative Group. Early goal-directed therapy in the treat-ment of severe sepsis and septic shock. N Engl J Med 2001; 345:1368-77.Sakr Y, Burgett U, Nacul FE, Reinhart K, 10. Brunkhorst F. Lipopolysaccharide binding pro-tein in a surgical intensive care unit: a marker of sepsis? Crit Care Med 2008; 36:2014-22.Carcillo JA, Fields AI; American College of Criti-11. cal Care Medicine Task Force Committee Mem-bers. Clinical practice parameters for hemody-namic support of pediatric and neonatal patients in septic shock. Crit Care Med 2002; 30: 1365-78.De Backer D, Hollenberg S, Boerma C, Goedhart 12. P, Buchele G, Ospina-Tascon G, Dobbe I, Ince C. How to evaluate the microcirculation? Report of a round table conference. Crit Care 2007; 11: R101.De Backer D, Verdant C, Chierego M, Koch M, 13. Gullo A, Vincent JL. Effects of drotrecogin alfa activated on microcirculatory alterations in pa-tients with severe sepsis. Crit Care Med 2006; 34:1918-24.Boerma EC, van der Voort PH, Ince C. Sublin-14. gual microcirculatory flow is impaired by the vasopressin-analogue terlipressin in a patient with catecholamine-resistant septic shock. Acta Anaesthesiol Scand 2005; 49:1387-90.Perner A, Jorgensen VL, Waldau T. Terlipressin 15. increased the concentration of 1-lactate in the rectal lumen in a patient with septic shock. Acta Anaesthesiol Scand 2004; 48:1054–7.

Morelli A, Rocco M, Conti G, Orecchioni A, De 16. Gaetano A, Cortese G, Coluzzi F, Vernaglione E, Pelaia P, Pietropaoli P. Effects of terlipres-sin on systemic and regional haemodynamics in catecholamine-treated hyperkinetic septic shock. Intensive Care Med 2004; 30:597-604.Ho KM. Combining sequential organ failure as-17. sessment (SOFA) score with acute physiology and chronic health evaluation (APACHE) II score to predict hospital mortality of critically ill pa-tients. Anaesth Intensive Care 2007; 35:515-21.Rivers EP, Kruse JA. The influence of early he-18. modynamic optimization on biomarker patterns of severe sepsis and septic shock. Crit Care Med 2007; 35: 2016-24.Kumar A, Schupp E, Bunnell E, Ali A, Milcarek 19. B, Parrillo JE. Cardiovascular response to dob-utamine stress predicts outcome in severe sepsis and septic shock. Crit Care 2008;12:R35. Trzeciak S, De Backer D. Modulation of the sep-20. sis inflammatory response by resuscitation: The missing link between cytopathic and hypoxic hy-poxia? Crit Care Med 2007; 35:2206-7.Kvolik S, Brozovic G, Harsanji-Drenjancevic 21. I, Azenic-Venzera D, Kristek G. More hemody-namic changes in hypertensive versus nonhyper-tensive patients during general anaesthesia for moderate invasive breast cancer surgery, a pro-spective randomized clinical study. Eur J Anaes-thesiol 2008; 25 (Suppl 44):4AP7-6.Scott EC, Ho HC, Yu M, Chapital AD, Koss W, 22. Takanishi DM Jr. Pre-existing cardiac disease, troponin I elevation and mortality in patients with severe sepsis and septic shock. Anaesth Intensive Care 2008; 36:51-9.Le Doux et al. Effects of perfusion pressure on 23. tissue perfusion in septic shock. Crit Care Med 2000; 28:2729-32.Kumar A, Roberts D, Wood KE, Light B, Parrillo 24. JE, Sharma S, Suppes R, Feinstein D, Zanotti S, Taiberg L, Gurka D, Kumar A, Cheang M. Dura-tion of hypotension before initiation of effective antimicrobial therapy is the critical determinant of survival in human septic shock. Crit Care Med 2006; 34:1589-96.Haršanji Drenjančević I, Ivic D, Drenjancevic D, 25. Ivic J, Pelc B, Vukovic D. Fatal fulminant sep-sis due to a cat bite in an immunocompromised patient. Wien Klin Wochenschr (2008) DOI 10.1007/s00508-008-0992-7.Meyer P, Pernet P, Hejblum G, Baudel JL, Maury 26. E, Offenstadt G, Guidet B. Haemodilution in-duced by hydroxyethyl starches 130/0.4 is similar in septic and non-septic patients. Acta Anaesthe-siol Scand 2008; 52:229-35.

41

Kvolik S. Pelc B. Farmakoterapija u JILu. In: 27. Jukić M. and coworkers, eds. Intenzivna medici-na. Zagreb: Medicinska naklada, 2008:406-42.Sennoun N, Montemont C, Gibot S, Lacolley P, 28. Levy B. Comparative effects of early versus de-layed use of norepinephrine in resuscitated endo-toxic shock. Crit Care Med 2007; 35:1736-40.Albanèse J, Leone M, Delmas A, Martin C. Ter-29. lipressin or norepinephrine in hyperdynamic sep-tic shock: A prospective, randomized study. Crit Care Med 2005; 33:1897–902.Russell JA, Walley KR, Singer J, Gordon AC, 30. Hébert PC, Cooper DJ, Holmes CL, Mehta S, Granton JT, Storms MM, Cook DJ, Presneill JJ, Ayers D; VASST Investigators. Vasopressin ver-sus norepinephrine infusion in patients with sep-tic shock. N Engl J Med 2008; 358:877-87.

Boyer A, Chadda K, Salah A, Annane D. Gluco-31. corticoid treatment in patients with septic shock: effects on vasopressor use and mortality. Int J Clin Pharmacol Ther 2006; 44:309-18.Thompson BT. Glucocorticoids and acute lung 32. injury. Crit Care Med 2003; 31(Suppl 4):S253-257.Sprung CL, Annane D, Keh D, Moreno R, Singer 33. M, Freivogel K, Weiss YG, Benbenishty J, Kalen-ka A, Forst H, Laterre PF, Reinhart K, Cuthbert-son BH, Payen D, Briegel J; CORTICUS Study Group. Hydrocortisone therapy for patients with septic shock. N Engl J Med 2008; 358:111-24.Wheeler AP, Bernard GR. Treating patients with 34. severe sepsis. N Engl J Med 1999; 340: 207-14. Vraneš J, Drenjančević D. New treatment pos-35. sibilities and future directions for sepsis therapy. Pharmaca 2001: 39:97-109.

Kvolik et al Blood pressure in sepsis