REVIEW ARTICLE

Sepsis and the Kidney

SC Tiwari*, Sanjay Vikrant**

The hosts reaction to invading microbes involves a rapidly amplifying polyphony of signals and responses that may spread beyond the invaded tissue. Fever or hypothermia, tachypnoea and tachycardia often herald the onset of sepsis, the systemic inflammatory response to microbial invasion. When counter regulatory control mechanisms are overwhelmed, often as the microbe moves from a local site to invade the blood stream, homeostasis may fail, and dysfunction of major organs may supervene. Further, failure of counterregulatory control leads to septic shock, which is characterized by hypotension as well as organ systems dysfunction. As sepsis progresses to septic shock, the risk of dying increases substantially. Early sepsis is usually reversible, whereas patients with septic shock, often succumb despite aggressive therapy1. The systemic inflammatory response syndrome (SIRS), as defined by critical care specialists, may have an infectious or a non-infectious aetiology.

4. Leucocyte count of > 12,000/uL or < 4000/uL or > 10% bands Sepsis Severe sepsis SIRS that has a proven or suspected microbial aetiology Sepsis with one or more signs of organ dysfunction, hypoperfusion, or hypotension such as metabolic acidosis, acute alteration in mental status, oliguria, coagulation abnormalities or adult respiratory distress syndrome. Systolic blood pressure < 90 mmHg or 40 mmHg less than patients baseline blood pressure in absence of other reasons for hypotension. Sepsis with hypotension that is unresponsive to fluid resuscitation plus organ dysfunction or perfusion abnormalities as listed above for severe sepsis. Septic shock that lasts for > 1h and does not respond to fluid and pressure administration. Dysfunction of more than one organ, requiring intervention to maintain homeostasis.

Hypotension

Septic shock

Refractory septic shock

Definitions in sepsis
Colonization

2,3

Microbiological event (Presence of bacteria, viruses, fungi, with no host response. Microbiological event (caused by bacteria, viruses, fungi) inducing some host response or presence of these microorganisms in a normally sterile tissue (CSF, peritoneum). Presence of viable bacteria (fungi) in the blood, as evidenced by positive blood cultures. Systemic illness caused by spread of microbes or their toxins via the blood stream. At least 2 of the following 4 conditions 1. Oral temperature of > 38 or < 36 C; 2. Respiratory rate of > 20 breaths/min or Pa CO2 of < 32 torr; 3. Heart rate of > 90 beats/min;

Multiple organ dysfunction syndrome (MODS)

Pathophysiology of the sepsis syndrome

Sepsis is a common and important cause of mortality in critically ill patients. Since the recognition that bacterial toxins were associated with infection, we have come a long way in our understanding of this condition and its pathophysiology. As research continues, we increasingly realise the complexity of the septic process, an appropriate and necessary body response to infection or insult, which can become excessive and detrimental if control is lost. The resultant uncontrolled immunological host response may lead, on a downward spiral, to tissue damage and multiorgan failure3. Infectious insults (such as endotoxins, exotoxins, and cell wall components of gram positive bacteria, viruses, fungi) as well as non-infectious insults (such as cellular debris, complement products, immune complexes) are capable of stimulating the host immune system to produce a number of important mediaters such as cytokines, eicosanoids complement and coagulation components, kinins, platelet

Infection

Bacteraemia (fungaemia)

Septicaemia

Systemic inflammatory responce syndrome (SIRS)

* Professor ** Senior Resident Dept. of Nephrology, AIIMS, New Delhi-110 029

activating factor, nitric oxide (NO), oxygen radicals and other mediators that can have profound effects on vascular tone and permeability, resulting in microcirculatory disturbances and finally shock and organ dysfunction4,5. Sepsis develops by way of a complex cascade of events triggered by certain initiating factors and involving several key players, multiple mediators, and elaborate feedback loops and interactions at all levels3 (Table I). Table I : Elements involved in the sepsis cascade
Process Infection Initiating factors Cell recruitment Cytokine release Mediator Septic shock MOF Elements involved

lysosomal proteases in close contact to the endothelium, thus enhancing vascular permeability, which may result in a generalised capillary leakage with interstitial oedema formation. Persistent systemic hypotension associated with severe microcirculatory disturbance due to capillary leak and impaired oxygen extraction results in tissue hypoperfusion and hypoxia. If this cascade is not interrupted, it will results in acute renal failure, cardiovascular and pulmonary insufficiency and finally multiple organ dysfunction4,6 Fig. 1, 2.
SEPSIS/SIRS Humoral Systems Cellular system Leukocytes, mast cells Monocytes, macrophages, Endothelial cells PLA2 Cytokines NO Endothelin

endotoxin, exotoxin, teichoic acid... monocyte, macrophage, PMN, endothelial cell... TNF-, IL-1, IL-6, IL-8, IL-10, TNF-... Coagulation factors, proteases, eicosanoids, PAF, NO...

Complement Kallikrein-Kinin Coagulation- and fibrinolytic system TXA2., PG,LT PAF

XIIa

Thrombin C3a, C5a C5b-9 ICAM-I ELAM GMP-140

Selections Integrins PMN Cell

O2 radicals Proteases
Vasocontricition/vasodilation Proteolytic destruction Capillary leak Tissue hypoxia

The initial phase of SIRS and sepsis is characterized by a generalized overwhelming production of proinflammatory humoral mediators, which belong to the cytokine network, complement system, coagulation and fibrinolytic system (Fig. 1). At the same time, there is activation of neutrophils, mononuclear cells, endothelial cells, and other cells of host defense system. Inflammatory mediators of humoral and cellular origin activate and damage the endothelial cells, which leads to dysfunction of the endothelium and stimulate the synthesis of vasoactive mediators. These mediators are responsible for vasoconstriction (endothelin-1) as well as for vasodilation (PGI2, NO) in the circulation which is often accompanied by septic shock. Nitric oxide (NO), synthesis induced for example by endotoxin, not only causes severe hypotension and vascular hyperactivity to vasoconstrictor agents, but also inhibits important enzymes involved in cellular respiration. The increased expression of adhesive molecules by endothelial cells as well as by phagocytes aggravates polymorphonuclear (PMN) mediated tissue injury. Activated leukocytes release toxic oxygen radicals and
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Abbreviations are : SIRS systemic inflammatory response syndrome, TXA2- thromboxane A2, PGI2- prostacyclin, LT- leukotrienes, PAF- platelet activating factor, NO-nitric oxide, PLA2- phospholipase A2, ICAM-I-intercellular adhesion molecule, ELAM-endothelial leukocyte adhesion molecules, GMP-140- granule membrane protein 140

Fig. 1: Sequence of pathomechanisms and mediator release in sepsis/ SIRS

Multi-organ failure (MOF) generally follows a predictable course, beginning with involvement of lungs, followed by hepatic, intestinal and renal failure, in that order. Haematologic and myocardial failure occur at a later stage. Alteration in central nervous system can occur early or late. Infection has been suggested to play a central role in induction of multiorgan failure (MOF)7.

Organ failure as a consequence of mediator inhibitor imbalance

In parallel to the inflammatory response to the inciting injury, the body mounts an anti-inflammatory response. This opposite response was defined by Bone as Compensatory anti-inflammatory response
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syndrome (CARS)8. The agents participating in CARS include interleukins (IL-4,-10,-11,-13), transforming growth factor- (TGF-), colony stimulating factors (CSF), soluble receptors to tumour necrosis factor (sTNFR), and receptor antagonists to IL-I (IL-Ira). It has been shown that some of these mediators, especially some of the interleukins, have profound effects on monocyte function, including antigen presenting activity. They also inhibit, T and B lymphocyte activity including antigen specific Tlymphocyte proliferation that results in immune suppression.
Pathogenesis of human septic shock
Nidus of infection Pneumonia Peritonitis Cellulitis Abscess Other infection sites Organisms Organism Toxins Structural components Exotoxin (TSST-1, Toxin-A) Endotoxin Cytokines Interleukin in 1,2,6,8 Tumor necrosis factor (TNF) Platelet activatory factor (PAF) Arachidonic acid metabolites Humoral defence systems Complement Kinins Coagulation Others Myocardial depressant substance (MDS) Endorphin Histamine Myocardium Depression Dilatation Vasculature Vasodilation Vasoconstricition Maldistribution of blood flow Endothelial destruction Severety depressed SVR Perfusion failure Multiorgan failure Death
Abbreviations are : CO- cardiac output, SVR-systemic vascular resistance

the anti-inflammatory response modulates the proinflammatory cascade and how they interact in the local milieu, high concentration of both mediators predicts poor outcome4.
Imbalance of SIRS and CARS CARS IL-4, IL-10, IL-11, IL-13 sTNFR, IL-Ira TGFb , CSF, etc HLA-DR

SIRS TNF-IL-1, IL-6 PAF, Lts, TXA2 O2-radicals C5a, etc

Immunosuppression

Homeostasis

Hyperinflammation

Abbreviation are : TNF-tumor necrosis factor IL-interleukin, LTs-Leukotriens, PAF-platelet activating factor, TXA2- thromboxane A2, sTNFR-soluble TNF receptor, IL-Ira- IL-1 receptor b antigonist, TGF-b - transforming growth factor- , CSF-colony stimulating factor.

Fig. 3 : Imbalance of pro-inflammatory and anti-inflammatory mediators may result either in SIRS (systemic inflammatory response syndrome) with uncontrolled hyperinflammation or CARS (compensatory anti-inflammatory response syndrome) characterised by immunosuppression.

Renal alteration in septic patients

Acute renal failure (ARF), the most common renal manifestation of sepsis, is not an isolated event but often a component of MODS that may complicate sepsis, indicating that similar mechanisms are operative in inducing the dysfunction of various organ system. Sepsis and particularly septic shock are important risk factors for the development of acute renal failure (ARF). Considering the fact that sepsis in various guises accounts wholly or in part, for more than 50% of cases of ARF, surprisingly little is known about the pathogenesis of this dysfunction. Most knowledge relating to renal pathophysiology in sepsis has been derived from animal experiments. Extrapolation of experimental findings to the human model is fraught with difficulties because most animal models are, unlike human disease, acute models using endotoxin or live bacterial infusion. The renal response in various animal models may, in addition, vary due to species differences. Moreover, usually the effects of gram negative bacteria or their products have been studied, whereas gram positive micro-organisms are increasingly involved in human sepsis10.

Depressed CO Hypotension Recovery

Fig. 2 : Schematic diagram represents the present understanding of the interrelationship in the pathogenesis of septic shock in humans9

The fact that these mediators can down regulate their own synthesis provides a mechanism through which homeostasis can be restored. If the compensatory antiinflammatory reaction is sufficiently severe, it will manifest clinically as anergy and increased susceptibility to infection. If the interaction between pro-inflammatory and anti-inflammatory mediators are unbalanced, SIRS or CARS will ensue (Fig. 3). Though it is not known how

Renal haemodynamics in septic acute renal failure

During severe sepsis, in addition to overwhelming

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production of inflammatory humoral mediators and activation of cellular system, there is activation of sympathico-adrenal axis with increased plasma levels of (nor) epinephrine, of renin-angiotensin aldosterone system (RAAS) with elevated levels of angiotensin II and a rise in vasopressin levels are often part of host response. These mechanisms are largely responsible for the clinical manifestations of sepsis, including the haemodynamic alterations that are characterised by vasodilation, a hyperdynamic circulation and microcirculatory changes contributing to inefficient oxygen extraction10.

advancing sepsis with cardiac depression), disproportionate renal vasoconstriction occurs. The investigations to date, have failed to demonstrate consistent results. Currently, it would appear that the main determinant of renal blood flow in sepsis is the state of systemic circulation, but there may be relative renal vasoconstriction in some circumstances.

Regional renal blood flow

If it is sufficiently severe and prolonged, global hypoperfusion can alone be responsible for acute tubular necrosis. But this does not appear to wholly explain sepsis associated ARF, since tubular damage can occur both experimentally and clinically even in the presence of well preserved renal blood flow and MAP. In addition, Van Lambalgen et al noted that a similar reduction in renal blood flow in animal models of septic and non-septic shock, resulted in significantly worse renal function in the septic group16. One explanation would be an inter-renal redistribution of blood flow. Shift of blood flow away from (mainly cortical) glomeruli would be expected to reduce glomerular filtration in these nephrons. A shift away from medulla, will place the medullary tubular segments, which are normally on the borderline hypoxia, at the risk of ischaemic damage. There are again conflicting experimental results regarding the nature of this postulated redistribution. Cronewell and Lindenauer demonstrated a shift in blood flow towards the juxtamedullary cortex from outer cortex17; this may explain the inappropriate polyuria, through washout of medullary concentration gradient observed in experimental sepsis and in a small proportion of patients with early hyperdynamic sepsis. Ravikant and Lucas however, demonstrated an increase in cortical blood flow without an increase in medullary flow18 and Stone et al, showed an increase in blood flow to the outer cortex at the expense of the inner cortex19. All the above studies used microsphere trapping. Microspheres will only be trapped in vessels of sufficiently small calibre, and may pass through dilated vessels or shunts and thus not accurately reflect blood flow. Garrison et al, using doppler fluximetry, demonstrated a shift from cortex to medulla, which was exacerbated by NO inhibition20. However, Cortez et al, measuring regional blood flow with radioactive xenon in septic
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Global renal blood flow

The effect of sepsis on systemic vasculature is ultimately to cause reduction in mean arterial pressure (MAP). In normal circumstances, when blood pressure falls autoregulation will act to maintain renal blood flow (RBF), increasing the proportion of cardiac output going to the kidneys. When mean arterial pressure falls below the auto-regulatory range in haemorrhagic or cardiogenic shock, renal vasoconstriction will occur. In experimental model of sepsis as well as in septic patients a wide variation in renal blood flow has been documented11. Lucus et al, measured ERPF in 40 septic patients by PAH extraction technique and showed a fall to 71% of the expected normal value. In 11 of these patients, a direct measurement of PAH extraction was made and corrected ERPF was increased to 154% with a range of 43-286% i.e., both vasoconstriction and vasodilatation. In 6 patients in whom RBF and CO were measured, the RBF/CO ratio was 19.2%, which is comparable to the ratio in health12. Rector et al, documented similar findings in 22 patients with GI sepsis. ERPF by PAH clearance was 73% of the predicted normal value. In 6 patients, using corrected PAH measurements, this again rose to 171% with a range of 51-276% RBF/CO ratio measured in 4 patients was 21%13. In contrast, Tristani and Cohen using indicator dilution techniques14 and Brenner et al, using a thermodilution catheter to measure the RBF15, showed reduction in RBF to < 10% of cardiac output, suggesting relative vasoconstriction. These opposing findings can be partially reconciled that in early hyperdynamic resuscitated sepsis, RBF increases in parallel with increasing CO, but that when a fall in CO occurs (either from inadequate fluid resuscitation or
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patients21 and Kirkebo and Tyssebotn, using hydrogen clearance measured by intra-renal electrodes in an endotoxic shock dog model, did not show redistribution of blood flow within the kidney22. Wang et al; using colloidal carbon infusion and laser doppler flowmetry in a septic rat model23, showed an increase in renal cortical blood flow in early sepsis (5 hrs) followed by a reduction at 20 hrs. Thus it may be that any changes are phasic and depend on the duration or severity of sepsis.

Fourthly, activation of the coagulation cascade by microthrombi, leading to alteration in intrarenal blood flow11.

Glomerular changes
The most significant alteration in glomerular function in sepsis is a decrease in glomerular filtration rate (GFR)24. In many cases this is determined by a fall in renal plasma flow and glomerular perfusion pressure, in the context of systemic hypotension. However, the renal ischaemia is by no means a uniform feature of sepsis. A fall in GFR due exclusively to a reduction in the filtration fraction has been described in experimental sepsis, and may well occur in septic patients. The main determinants of filtration fraction (FF) are the balance between the resistances of the afferent and efferent glomerular arterioles, and the total surface area for filtration. Constriction of the afferent arteriole and/or dilation of the efferent arterioles, will reduce the FF. Vasoactive substances which are released during sepsis, and which cause preferential afferent constriction, include leukotrienes, adenosine, thromboxane A2 and endothelin. The reduction in the surface area for filtration as an effect of vasoactive mediators involved in sepsis, has been described. These include leukotrienes thromboxane A2, and angiotensin II11.

Additional considerations in sepsis

Some other features of sepsis are worthy of consideration in relation to renal blood flow. Firstly, in the context of clinical sepsis induced ARF, which is frequently associated with failure of other organs, that the acidosis, hypoxia and mechanical ventilation, most notably PEEP, are all known to effect renal blood flow, causing vasoconstriction. Secondly, the role of inotropic agents is less clear. Without being sure if the renal circulation is inappropriately dilated or constricted in sepsis, it is difficult to judge if a given agent will be therapeutic or deleterious. While infusion of dopamine causes renal vasodilation in health, this is not proven in sepsis. In a clinical study, it was found that infusion of adrenaline or noradrenaline initially reduces RBF, in a healthy animal, the effects in sepsis are less marked. The combination of dopamine with adrenaline did not influence the RBF changes observed with adrenaline alone. Hypoxia attenuates the increase in ERPF induced by dopamine in normal subjects. Indeed, it can be questioned whether renal vasodilatation is a useful therapeutic manoeuvre, since sepsis-induced dilatation may already have reduced perfusion pressure, and thus the glomerular filtration rate. Secondly, increased body temperature worsens ischaemic renal injury and ATP losses during shock. Thirdly, neutrophils have been shown to accumulate in the ischaemic kidney. They may be activated by acute renal failure per se, and in an additive fashion by sepsis and by renal hypoperfusion without ARF. The addition of neutrophils primed by endotoxin to a kidney rendered mildly ischaemic, results in severe injury. Since renal oxygen extraction is reduced in sepsis, it can be appreciated how in some circumstances, sepsis could induce renal damage with minor of absent changes in renal blood flow.

Endothelial Injury
In common with vascular beds elsewhere, there is the potential for glomerular capillaries to be affected by acute endothelial injury. This is linked to activation of the coagulation system by endotoxin, release of tissue factor, deposition of platelets and fibrin within capillaries, and reduced fibrinolytic activity in affected capillaries. In addition, activated neutrophils and a range of cytokines, such as IL-Ib, TNF and platelet activating factor, are also implicated in the pathogenics of endothelial injury. Both experimental and human studies support the occurrence of capillary microthrombi in acute renal failure (ARF) caused by sepsis25.

Other glomerular lesions

It is known that infection is a potent trigger of immunological mechanisms which may produce acute glomerular inflammation. Acute proliferative
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glomerulonephritis has been described in septic patients, primarily in relation to localized abscess formation, and in patients with bacterial or rickettsial endocarditis. Infection is also frequently implicated in the initiation of vasculitic diseases, or in causing a relapse of quiescent vasculitis. In the kidney, these diseases usually manifest as a focal necrotising glomerulonephritis often with glomerular epithelial crescents. Numerically, the most important are Wegener s granulomatosis and microscopic polyarteritis, but others, including Henoch-Schonlein disease, polyarteritis nodosa, systemic lupus erythematosus and Kawasaki disease, may also present in context of active infection. Rarely, Goodpastures syndrome with anti GBM antibodies (glomerular basement membrane antibodies) may be triggered by sepsis11.

has under-pinned the current trend towards the use of continuous modes of replacement therapy in septic patients26.

Other insults
It is possible, but relatively difficult to induce severe tubular injury from ischaemia alone. Similarly, endotoxin alone is not a powerful inducer of tubular injury and has inconsistent effects on structure and function of the isolated perfused kidney. It is likely that in most patients with sepsis and acute renal failure, multiple insults are involved. For example, synergy has been demonstrated between endotoxin and aminoglycoside antibiotics in terms of their effect on renal function 27. Renal failure can be induced by conventional therapeutic blood levels of gentamicin when combined with endotoxin infusion28. Similarly, non steroid anti-inflammatory drugs, which have little effect on normal renal function, are well recognised as causing rapid development of oliguria and renal failure in septic patients. Moreover, drugs including NSAIDs and antibiotics can also cause renal failure through the development of acute allergic interstitial nephritis, with associated tubular damage29.

Tubular Injury
Patients with established acute renal failure due to sepsis are generally regarded as suffering from acute tubular necrosis. There is evidence that in many cases, this is indeed true. In addition to renal blood flow, arterial oxygenation and haemoglobin concentration are important determinants of renal oxygen delivery (Fig. 4). Renal oxygen extraction may be impaired in a septic patient and renal O 2 requirements may be initially high, because of active tubular sodium absorption11.
(Reduced) renal + Renal arterial 02 saturation + Haemoglobin concentration blood flow Renal O2 delivery + Renal O2 extraction + Renal O2 requirement (metabolic activity)

Sodium retaining acute renal failure

The functional hallmark of acute tubular necrosis is a failure to reabsorb filtered sodium which appears in the final urine (Fractional sodium excretion FENa). However, clinical and experimental studies have documented the presence of a reduced FENa (< 1%) in septic acute renal failure, indicating the presence of stimulated tubular sodium reabsorption 30 . In experimental sepsis this pattern of tubular function has persisted for upto 48 hrs after the initiation of systemic sepsis, and renal hypofiltration has been shown to occur in presence of maintained arterial pressure and blood volume, and with normal renal plasma flow. This correlated strongly with systemic vasodilatation and increased cardiac output. In this respect there are similarities to the pattern of renal function seen in advanced hepatic cirrhosis and it has been suggested that a neuroendocrine response to perceived relative under filling of the dilated

Determine Oxidative stress tubular cell membrane damage lipid peroxidation Cell swelling, Tubular obstruction Filtration failure

Figure 4 : Pathophysiology of acute tubular necrosis in septic patients

Once established, the tubular damage may be perpetuated or worsened by haemodynamic disturbances occurring during the course of acute renal failure, which in some cases may be associated with intermittent dialysis treatment. This observation
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vascular tree, is common to both conditions.

Pathophysiology of acute renal failure in septic shock: from pre-renal to renal failure
Table II : Mechanisms of pre-renal acute renal failure
MAP < 80 mmHg (below normal autoregulation limit) MAP 80-90 mmHg plus impaired autoregulation Age, arteriosclerosis, diabetes Renal artery stenosis and ACE inhibitor Renal vasoconstriction Norepinephrine, endothelin Radio contrast Prostaglandin, synthesis inhibitors Endotoxin

also a strong predictor of short and long term mortality. Case fatality rates are similar for culture positive and culture negative severe sepsis and septic shock.* It is known that advancing age and prior chronic disease may diminish physiological reserve and predispose to sepsis and MOF. In 360 patients with ARF by Brivet et al; ARF was related to sepsis in 48% and septic patients were older (63 1.4 years) and had a higher mortality rate than non septic patients (73% vs 45%). In ARF as part of MODS, mortality increases according to the number of organs in failure 32,33 . In a retrospective study of ARF of septic origin, overall mortality was 74%. 76.6% of patients died due to sepsis. On univariate analysis, the hospital mortality was linked to age, pneumonia, peritonitis, number of failing organs and late oliguria. On multivariate analysis three variables related to outcome were identified age over 60 years, respiratory failure and haemodynaic failure34. The combination of pulmonary and renal failure is particularly life threatening.

Endotoxaemia initially causes a pre-renal type of ARF (renal vaso-constriction); sepsis then leads to the full picture of tubular/obstructive acute renal failure. This syndrome results from an intricate array of pathophysiological mechanisms. No unifying concept has emerged that would allow prevention at a single key step. Rather, the mechanisms of hypotension/ Ischaemia, endotoxin/cytokines, oxidant injury, vasoconstriction and the use of nephrotoxic antibiotics need to be addressed as they occur, individually or in conjuntion31 (Table II, III). Table III : Main pathogenetic mechanisms of tubular/obstructive ARF
Hypotension/Ischaemia Decreased glomerular ultrafiltration coefficient Tubular damage tubular obstruction Afferent-efferent imbalance Tubular back leak Medullary capillary congestion Endotoxin/cytokines Direct vasoconstrictor effects Enhancement of tubular damage Delay of recovery phase

Laboratory findings
In early sepsis, abnormalities may include leukocytosis with a left shift, thrombocytopenia, hyperbilirubinaemia, and proteinuria. Leukopenia may develop. The neutrophils may contain toxic granulations, Dohle bodies, or cytoplasmic vacuoles. As the septic response becomes more severe, thrombocytopenia worsens, coagulation abnormalities suggesting of DIC, azotaemia, hyperbilirubinaemia become prominent alongwith rise in levels of aminotransferases. Active haemolysis suggests clostridial bacteria, malaria, a drug reaction, or DIC. In the case of DIC, microangiopathic changes may be seen on smear. During early sepsis, hyperventilation induces respiratory alkalosis. With respiratory muscle fatigue and accumulation of lactate, metabolic acidosis (with an increased anion gap) typically supervenes. ABG reveals hypoxaemia, which is initially correctable with supplemental oxygen but later refractoriness to 100% 02 inhalation indicates right to left shunting. The chest radiograph may be normal or may show evidence of underlying pneumonia, volume overload or diffuse infiltrates of ARDS. The EKG may show only sinus tachycardia or non specific ST-T wave abnormalities.

Tubular/ Obstructive ARF

Nephrotoxic antibiotics

Oxidant injury Leukocyte adhesion Reperfusion injury

Vasoconstrictors Endogenous Therapeutic

Prognosis
Several prognostic stratification systems that factor in the age of the patient, underlying condition and various physiological variables yield estimates of the risk of dying of severe sepsis. Underlying disease most strongly influences the risk of dying. Septic shock is
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Most diabetics with sepsis develop hyperglycaemia, severe infection may precipitate diabetic ketoacidosis. Hypoglycemia occurs rarely. Serum albumin level, initially within normal range, declines as sepsis advances.

substrate delivery to the tissue. Measures include volume therapy, inotropic support, ventilatory therapy for progressive hypoxaemia, hypercapnia, neurological deterioration or respiratory muscle fatigue. Steroids may be indicated for adrenal insufficiency which should be considered in septic patients with refractory hypotension, fulminant N. meningitides bacteraemia, prior glucocorticoid thereby and disseminated tuberculosis.

Diagnosis
Definite aetiological diagnosis requires isolation of the micro-organism from the blood or a local site of infection. At least two blood samples (10 ml each) should be obtained (from different vene puncture sites) for culture. Because gram negative bacteraemia is typically low grade, multiple blood cultures or prolonged incubation of cultures may be necessary. If blood culture is negative, then Grams staining and culture of material from primary site of infection or from infected cutaneous lesions may help establish the microbial aetiology. With overwhelming bacteraemia, micro-organisms are sometimes visible on buffy coat smears of peripheral blood. Detection of endotoxin in blood by the limulus lysate test may portend a poor outcome.

Renal protection
There is no doubt that the best measure for preventing ARF in patient at the risk of developing MOF is timely and adequate resuscitation. Renal dose dopamine 1-3 ug/kg/min as renoprotective measure is still widely used. While dopamine is capable of increasing urine flow, it is unlikely that this is mediated purely via a direct vasodilatory action as originally purposed. Even at low doses, dopamine is capable of being both an inotrope and a vasoconstrictor, much of the increase in RBF being dependent upon an increase in BP or CO. Dopamine is also known to have a direct diuretic effect on the renal tubules. Contrary to popular belief, low dose dopamine is not without side effects, as it has been implicated for development of mesenteric ischaemia, pituitary suppression in animal models. Thus, if the intention is to increase RBF or perfusion pressure, better drugs like dobutamine and norepinephrine respectively should be used. Similarly, with loop diuretics and mannitol, there is danger that they are given to patients who remain hypovolaemic and who actually require more fluid. While these agents may prevent the development of oliguric ARF in some cases, there is little evidence that conversion from oliguria to polyuric state improves outcome. Nevertheless, the prevention of oliguria does make for, more manageable fluid balance35. Calcium antagonists have been used to combat calcium induced vasoconstriction in renal failure. While these agents may be beneficial in selected cases, they are not useful in the setting of MOF, not least because of their ability to worsen hypotension.

Treatment
Appropriate anti-microbial therapy Appropriate antimicrobial therapy given early on in course of an infective illness, improves the outcome. The choice of initial therapy is based on knowledge of the likely pathogens and available information about pattern of antimicrobial susceptibility among bacterial isolates from the community, the hospital, the patient. Pending culture results, empirical antimicrobial therapy that is effective against both gram positive and gram negative bacteria should be initiated. Maximal recommended doses of antimicrobial drugs should be given intravenously, with adjustment for impaired renal function when necessary. Removal of the source of infection Removal or drainage of a focal source of infection is essential. Haemodynamic, respiratory and metabolic support The primary goal is to restore adequate oxygen and

Nutritional or metabolic support

Experimental studies have shown that enteral nutrition
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may have a favourable effect on gastrointestinal immunological functions and infectious morbidity. Early enteral nutrition is associated with a decreased catabolic response to injury, maintenance of bowel mucosal integrity, decreased translocation, improved wound healing, and reduced septic morbidity rates. Enteral feeding should be the method used to provide nutritional or metabolic support whenever possible. Patients who are severely malnourished may require early administration of parenteral nutrition, particularly if the establishment of enteral nutrition is likely to be difficult. Nevertheless, it is possible to nourish upto 85-90% of patients who require metabolic support via enteral route, using a simple nasogastric tube35. Controversy surrounds the benefits or otherwise of any particular formulation. Immune enhancing nutrients such as arginine, glutamine, omega 3 fatty acids and purine nucleotides are undergoing investigation in clinical trials, but at present there is no consensus concerning their use36.

Theoretically, haemofiltration may contribute to an imbalance between pro- and anti-inflammatory mediaters, both of which may be essential as well as deleterious depending on their concentration and on the phase of the disease process. Animal studies in use of HF in (mostly hypodynamic) models of sepsis show an improved survival in 50% of the studies and, more consistently an improvement of myocardial function that is ascribed to the elimination of a myocardial depressant substance. Many uncontrolled clinical trials have found extra corporeal removal of inflammatory mediators, provide remarkable haemodynamic and respiratory stability and occasional improvement of septic patient on haemofiltration; however, decrease in plasma level of inflammatory mediators during CRRT more an exception than the rule. In two RCCT plasma level of TNF, IL-6 remain unchanged37. Improvement in survival or a reduction of organ failure during CRRT in patient with sepsis remains to be confirmed in RCCT. RCCT is useful tool to control azotaemia, electrolyte disturbances, administration of antibiotics, parenteral nutrition, pressure agents and other drugs without involving fluid overload36,37,38.

Extra-corporeal therapies
They include haemodialysis, haemofiltration or a combination of both (haemodiafiltration). All these modalities may be used as intermittent or continuous procedures. The superiority of one over the other is not established26. CRRT is recommended in following patients Unstable haemodynamic situation Being ventilated Anuric or MOF patients (fluid removal is easier) Cerebral oedema/hypoxia Drawbacks : Need for anticoagulation Expensive CRRT in sepsis and other inflammatory syndromes Improving the course of sepsis and inflammation by extra-corporeal removal of inflammatory mediators is indeed an attractive hypothesis. Although many inflammatory mediators have a molecular weight that is compatible with the convective removal through high flux membranes, extra-corporeal removal is limited by binding substances, membrane adsorption and due to very short half life with high endogenous clearance.

Plasma exchange
Along the line of elimination of adverse substances in septic patients, is the use of plasma exchange. Using this approach again, the problem of anticoagulation occurs. In addition, one really wonders whether removing every inflammatory mediator is of benefit for a septic patient26.

Immunotherapy
Monoclonal antiendotoxin antibody (MAb). If endotoxin is indeed a fundamental trigger for the rogue inflammatory response, it might be anticipated that monoclonal antibodies to endotoxin would be capable of inhibiting the tissue injury. Both murine (E5) and human (HA-IA) endotoxin monoclonal antibodies have been investigated in large controlled trials. In the case of HA-IA, initial reports of a reduction in mortality in a subgroup of patients with gram negative bacteraemia were not confirmed in large randomized controlled clinical trials (RCCTs)39. IL-Ira : Studies using the naturally occurring receptor antagonist of IL-I, failed to demonstrate efficacy in

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larger phase III RCCTs40. PAF antagonist : Two different antagonists of PAF have been investigated in sepsis with negative phase III results41. Murine TNF MAb and TNF soluble receptors: No benefit could be demonstrated42,43.

Nitric Oxide Synthase inhibitors

The massive release of nitric oxide has been implicated in many manifestations of sepsis6, such as the profound vasodilatation with refractory hypotension, the blunted response of vascular smooth muscle to catecholamines in septic shock and myocardial depression. Excessive amounts of NO may be directly cytotoxic through the formation of free radicals (peroxynitrite radical in particular). The pathophysiologically increased NO production occurs due to excessive induction of the inducible NO synthase (iNOS), probably caused by bacterial endo and exotoxins as well as by an increase of circulating pro-inflammatory cytokines. The enzyme NO synthase (NOS), is present in at least three forms. Neuronal nitric oxide synthase (nNOS) and endothelial nitric oxide synthase (eNOS) are both present in healthy cells and are calcium dependent whereas inducible NO synthase (iNOS) is calcium independent. Experimental studies have confirmed that NO production causes severe hypotension in septic animals. Treatment with competitive NOS inhibitors abolishes the hypotension in animal as well as in septic patients. However, this use is complicated by concomitant decrease in cardiac index and oxygen delivery44. The L-mono-methyl form of arginine (L-NMMA) is an L-arginine analog that can inhibit all form of NOS. This agent (546C88) is presently undergoing assessment by Glaxo Wellcome in a large (4000 patients) phase III study of septic shock. It has already been assessed in a phase II study of safety and efficacy in 312 patients with refractory septic shock 45. Although, survival was no different at 14 and 28 days, a greater proportion of patients treated with L-NMMA (546C88) had reversal of shock (39% vs 24% respectively P < 0.005) and were independent of vasopressor support at 72 hrs after randomization compared with patients treated conventionally. As with norepinephrine (which was used in both

treatment and control groups to maintain mean arterial pressure), concern surrounds inappropriate dosing that might result in intense vasoconstriction shutting down the micro circulation of various organ systems. A particular worry has been the effect of LNMMA on pulmonary circulation46, with a number of reports of severe pulmonary hypertension (usually in patients with chronic airway obstruction and an element of cor-pulmonale) leading to lethal right heart failure. From the renal perspective, animals studies have implicated a role for NO in the normal physiological regulation of renal haemodynamics and sodium excretion. Administration of L-NMMA to healthy volunteers is capable of reducing renal plasma flow and glomerular filtration rate 47 . This finding emphasizes the potential nephrotoxicity of excessive NOS inhibition and points to the need to find selective inhibitors of the inducible form of NOS in the future. Thus, NOS antagonism may well become a clinically relevant treatment for haemodynamic instability of sepsis in near future35.

Other therapies
Anti-oxidants (N-acetyl cysteine, procysteine, ketoconazole, pentoxifylline, naloxone, a bradykinin antagonist, antithrombin III, and steroids are just some of the other agents that have been used to combat the inflammatory process with limited or no success.

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