12RC1-MARX Volume replacement therapy in critically ill patients

Transcription

1 12RC1-MARX Volume replacement therapy in critically ill patients Christoph Thiele, Tim-Philipp Simon, Gernot Marx Department of Intensive Care and Intermediate Care, RWTH University Hospital, Aachen, Germany One of the therapeutic essentials in critically ill patients is efficient and goal-directed volume replacement therapy. In a volume deficient shock state depletion leads to a decrease in cardiac preload, resulting in a reduction of cardiac output, tissue hypoperfusion, tissue hypoxia, and finally in organ dysfunction. It is essential to restore the necessary plasma volume as quickly as possible by administration of volume replacement solutions in order to ensure adequate tissue perfusion and oxygenation. A variety of volume replacement solutions are available for fluid therapy in critically ill patients. Although numerous animal studies and large, multi-centre studies have been conducted precisely for this purpose, there is still no clear answer as to which volume replacement solution should be given preference. Recently, volume treatment in patients with severe sepsis or septic shock has been the subject of a considerable debate, especially because there have been increasing concerns about the safety of hydroxyethyl starch solutions for volume replacement in sepsis. Goals of volume therapy It is important to avoid hypovolaemia and hypervolaemia in the fluid therapy of critically ill patients. Goal-directed early fluid replacement in patients with severe sepsis and septic shock improves survival significantly. 1 One should take into account the specific disease and indication to determine the choice of the volume replacement regime of each patient. In a study on ICU patients, a lower mortality was achieved in patients with persistent shock by administering a greater volume. 2 On the other hand, restricting fluid therapy may benefit patients with acute pulmonary failure. 3 In all cases it is important to use clinical measurements to determine appropriate volume therapy. One of the widely used variables to assess the volume status of a patient is the central venous pressure (CVP). Rivers et al. used CVP in their much respected study to guide volume therapy, 1 and the guidelines of the Surviving Sepsis Campaign recommend a CVP of 8-12 mmhg as a target variable for volume therapy. 4 CVP is easy to determine clinically and is still standard practice with septic patients, but there are many factors that influence this indicator of cardiac preload. In patients with persistent shock it is important to start haemodynamic monitoring as soon as possible to guide goal-directed volume therapy. 5 There are several more or less invasive options for guidance; Pulmonary artery catheterization (PAC): There is currently much debate about the safety and benefit of its use to guide volume therapy. The development of alternative monitoring techniques especially for measurement of volume parameters has decreased routine use of the PAC. Patients with a high peri-operative risk, especially those undergoing cardiovascular surgery, may benefit from PAC monitoring intra- or postoperatively. 6 1/10

2 Transpulmonary thermodilution: Using this less invasive method it is possible to guide volume therapy by determining cardiac output and stroke volume variation. Additionally the global end-diastolic volume (GEDV) provides information about the cardiac preload and the extravascular lung water (EVLW) can indicate potential fluid overload. Oesophageal Döppler: This technique allows measurement of aortic blood velocities. Thus stroke volume and cardiac output can be calculated and intravascular fluid resuscitation can be guided by quantifying the increase in flow in response to fluid challenges. 7 Echocardiography: Apart from the invasive procedures mentioned above, this is also a good method to assess the volume status of a patient and to gain a simultaneous impression of cardiac function. Passive leg raising: This bedside test in combination with haemodynamic monitoring is easy to perform and can indicate the response of an individual patient to volume administration. 8 Volume replacement solutions Crystalloids Crystalloid infusion solutions contain only low molecular weight components and accordingly exhibit low colloid osmotic pressure (COP). Compared to colloid infusion solutions, this results in a markedly shorter intravascular half-life. Only approximately a quarter of the volume administered is retained intravascularly for an hour. 9,10 Diffusion into the interstitial space, which may occur due to the lack of oncotically effective components, results in interstitial oedema, which may hinder pulmonary and peripheral gas exchange. The short intravascular half-life also means that in comparison to colloid solutions a two- to four-fold volume needs to be administered to maintain plasma volume. The advantages of crystalloid infusion solutions are in particular their low cost and their low allergy potential. Nowadays, the most commonly used crystalloid volume replacement solutions are balanced full electrolyte solutions. Another common crystalloid is sodium chloride 0.9%, which is used often as a carrier solution for drugs or colloid volume replacement. Balanced solutions Full electrolyte solutions correspond to human blood constituents with regard to the concentration and osmolarity of sodium, potassium, calcium, chloride and, in part, magnesium. As crystalloid infusion solutions cannot, for valency reasons, contain bicarbonate, the administration of large volumes can quickly give rise to dilutional acidosis. Therefore they contain organic anions to replace the negatively charged proteins and the hydrogen carbonate in the plasma. For many years, the most commonly used full electrolyte solution was lactated Ringer's solution, which is, however, hypotonic relative to serum osmolarity. Furthermore, a large amount of oxygen is consumed when the lactate is metabolized. Balanced full electrolyte solutions containing acetate have been developed recently. As they are isoionic, iso-oncotic, isotonic and isohydric, their use hardly disturbs the electrolyte and acid-base balance. Recently, when comparing perioperative fluid replacement in patients with open abdominal surgery, the use of balanced crystalloid solutions caused fewer postoperative complications when compared to sodium chloride 0.9%. 11 In the meantime, colloids have also been made available in balanced carrier solutions. Different studies in past years have reported the advantage especially of balanced hydroxyethyl starch solutions over older products with sodium chloride 0.9% as the solvent. In 2010, Sümpelmann et al. observed 396 2/10

3 children in which the perioperative use of balanced HES solutions led to less disturbance of the acidbase balance compared to unbalanced HES solutions. 12 Aksu et al. demonstrated in an animal investigation the superiority of balanced as opposed to unbalanced HES in renal perfusion in septic rats. 13 Finally, in their comparison of different volume replacement solutions using a porcine two hit model, Simon et al. found that fluid therapy with balanced 6% HES 130/0.42 and lactated Ringer's solution led to a significantly lower base excess than the use of unbalanced 10% HES 200/0.5, suggesting that the carrier solution of colloid volume replacement solutions is relevant to avoiding disturbance of the acid-base balance. 14 Sodium chloride Sodium chloride 0.9% solutions contain only sodium and chloride ions. It has been recognised for a long time that sodium chloride 0.9% solution is not as physiological as its name would suggest. 15,16 Both its sodium concentration and in particular its chloride concentration, each at 154 mmol.l -1, lie well above human serum concentrations; so there is a risk of hyperchloraemic acidosis. This is because, with the infusion of large amounts of sodium chloride, the increase in the chloride concentration in serum is greater relative to the sodium concentration. The resulting reduction of the strong ion difference leads, due to electrochemical forces, to an increase in the hydrogen ion concentration and thus to the development of acidosis. 17 This manifestation of metabolic acidosis with simultaneous hyperchloraemia after volume replacement therapy with normal saline both in septic shock and in haemorrhagic shock and when used perioperatively is reported in numerous animal studies and clinical trials Guidet et al. come to the conclusion that there are no persuasive indications of a clinically relevant impact of hyperchloraemic acidosis on morbidity and mortality. 21 Handy and Soni also note that sodium chloride 0.9% has been used as a fluid replacement for 50 years without significant clinical complications. 22 On the other hand, Healey et al. report significantly increased mortality after volume therapy with sodium chloride 0.9% in experimental haemorrhagic shock. 23 Kellum observed in 2002 after fluid replacement with sodium chloride in septic rats that hyperchloraemia and the resulting metabolic acidosis were strongly associated with increased mortality in these animals. 24 There are different mechanisms of damage whereby metabolic acidosis may impact morbidity and survival. On one hand, effects on the cardiovascular system have been reported, such as reduced myocardial contraction strength, low peripheral vascular resistance and a weaker response to catecholamines. 20 Furthermore Kellum et al. demonstrated that hyperchloraemic metabolic acidosis may cause changes in inflammatory response In an observational study on perioperative volume replacement therapy in general surgery patients, the risk of postoperative infection was significantly increased, when sodium chloride was used. 11 One possible explanation is that hyperchloraemic acidosis induces cytokine expression, as observed by Kellum in septic rats. 28 In several studies, it has also been found that use of sodium chloride 0.9% increases the need for blood products, and so it must be assumed that hyperchloraemic acidosis also impairs coagulation. 11,29 Renal function may also be affected by the infusion of large amounts of sodium chloride. An unphysiologically high chloride content causes not only decreased natriuresis but also renal vasoconstriction and reduced secretion of renin. 22,30 Recently, in an Australian prospective clinical trial with 760 ICU patients Yunos et al. showed that a chloride-restrictive strategy of intravenous fluid administration led to a significant decrease in the incidence of acute kidney injury and the use of renal replacement therapy. 31 In a view of the hazards of 3/10

4 hyperchloraemic acidosis and the recent clinical evidence, we suggest using balanced solutions instead of sodium chloride only and sodium chloride based solutions. Colloids In general, colloid volume replacement solutions are an effective and readily available form of plasma replacement. Colloid solutions contain high molecular weight substances. Compared to crystalloid solutions, they provide a markedly higher COP and a markedly longer intravascular half-life, as the colloids cannot diffuse freely through the capillary membranes. A distinction is made between synthetic and natural colloid infusion solutions. Human albumin and fresh frozen plasma in particular are used as natural colloid infusion solutions. Gelatin and hydroxyethyl starch are used as synthetic colloids. The high oncotic force of colloids results in a high water binding capacity and thus a positive effect on blood volume. In a clinical trial in which treatment with colloids in both septic and non-septic patients produced better values in terms of the heart filling, cardiac output, strength of the heartbeat and oxygen delivery compared to treatment with crystalloids. 32 Animal trials have also demonstrated the superiority of colloid solutions in maintaining plasma volume. 33 Magder et al. evaluated the usefulness of colloid infusions for volume resuscitation in patients after cardiac surgery. They used a nurse-delivered flow-based algorithm to guide volume therapy in this randomized double-blind, control trial. The authors demonstrated that the use of a colloid solution for volume resuscitation significantly improved haemodynamic status in this kind of patient. Further they found that patients treated with hydroxyethylstarch had significant less pneumonia and mediastinal infection and less cardiac pacing. They reported no differences in renal function. 34 James et al. compared the volume therapy with HES 130/0.4 and with sodium chloride 0.9% in patients with severe trauma. This South-African study even demonstrated improved renal function and lactate clearance after administration of the modern HES solution compared to sodium chloride 0.9% in patients with penetrating trauma. 35 These results underline that the indication for the use of colloids is the immediate treatment of shock. Human albumin Albumin is the protein with the highest concentration in human plasma and as the primary endogenous colloid it is largely responsible for the maintenance of colloid osmotic pressure. It is extracted from human plasma as colloid volume replacement and then, inter alia, undergoes viral inactivation. Compared to crystalloid and synthetic colloids, however, human albumin has no advantages, 36 but is more costly. Its use in volume therapy in critically ill patients is therefore not recommended. 37 This has also been confirmed by the results of the large multi-centre SAFE study in which no differences in terms of morbidity and mortality were established after volume therapy with 4% albumin compared to 0.9% sodium chloride in 7000 ICU patients. In the subgroup of patients with craniocerebral trauma a worse outcome was observed. 38 Furthermore, a large observational multi-centre study in 2008 by Schortgen et al. demonstrated that the use of hyperoncotic human albumin is associated with an increased incidence of kidney damage and a higher 28-day mortality. 39 4/10

5 Gelatin Gelatin is a product of higher molecular weight collagen and has a molecular weight of approximately 35 kda. It is present in solutions in concentrations of between 3.5% and 5.5%. As the COP of these preparations is only slightly higher than the physiological COP of plasma, the effect on blood volume and the intravascular half-life are lower compared to currently used HES preparations. The main disadvantage of gelatin is the risk of allergic reactions. 40 A distinction must be drawn here, however, between the urea-linked gelatin with a rate of allergic reactions of up to 10%, and the modified liquid gelatin and oxypolygelatin with markedly lower potential for allergy. Due to the increasing concerns regarding the use of hydroxyethyl starch, especially in sepsis (see below), gelatin is once again being used more. In a meta-analysis, Saw et al. found that gelatin has advantages compared to HES preparations in relation to the incidence of acute renal failure in critically ill patients and when used perioperatively. 41 However, in general, the data available regarding the use of gelatin in critically ill patients are not very extensive. For this reason we need large clinical trials to evaluate the use of gelatin in critical ill patients. Hydroxyethyl starch Hydroxyethyl starch is a synthetically produced polymer made from waxy maize starch and potato starch and which therefore predominantly consists of amylopectin, and thus of branched chains of glucose molecules. The glucose units are partially hydroxyethylated. In the body, HES is cleaved by hydrolysis by alpha-amylase and either metabolized or eliminated by the reticuloendothelial system or excreted via the kidneys. A molecular weight of kda is considered the renal threshold for glomerular filtration. The various HES preparations differ in their molecular weight, concentration, degree of substitution and substitution pattern. The HES solutions used in recent years have a molecular weight of kda. HES concentrations in common use are 6% (=iso-oncotic) and 10% (=hyperoncotic). By degree of substitution is meant the proportion of glucose units that are hydroxyethylated. The fraction substituted is usually The substitution pattern refers to the ratio of glucose units substituted at carbon 2 and 6. Commercially available HES solutions have a C2:C6 ratio of 5:1 to 9:1. The initial effect of HES on plasma volume is essentially in proportion to the concentration, but the intravascular half-life and therefore the effect over time depends upon the molecular size and the degree of substitution or the substitution pattern. The higher the molecular weight and the greater the degree of substitution, the slower the elimination, 42 and repeated administration of such preparations results in increased accumulation of HES in the serum. 43 This is a further reason, in addition to a potential impairment of coagulation and renal function, why there are increasingly concerns about the safety of hydroxyethyl starch, and why its use in critically ill patients, especially in sepsis, is currently a subject of much debate. Hydroxyethyl starch in sepsis As indicated already, many studies have raised concerns about the safety of hydroxyethyl starch solutions for volume replacement in sepsis. In a French multi-centre study Schortgen et al. reported 2001 the use of 6% HES 200/0.62 as an independent risk factor for the occurrence of acute renal failure in patients with severe sepsis and septic shock. 44 In this study Schortgen used 2 nd generation hydroxyethylstarches with a molecular weight of 200 and a molar substitution of In the discussion about the safety of HES different starches with different kinetic properties were compared often mistakenly. As described above in the kinetic properties of HES solutions the molecular weight and the 5/10

6 molar substitution has a large impact on elimination and volume effect. In the multi-centre VISEP study HES 200/0.5 also a second-generation starch were compared with lactated Ringers solution. In this study a significantly higher rate of renal failure was observed in patients who had been treated in septic shock with 10% HES 200/ This study has also been criticised in two respects in particular: on the one hand, approximately 80% of the patients had already been haemodynamically stabilized at enrolment in the study as part of goal-directed therapy. On the other hand, the amounts of hydroxyethyl starch infused markedly exceeded the approved maximum dosage. 46 The results of an observational study on 3147 critically ill patients in European ICUs, however, in whom, inter alia, the reasons for the need of renal replacement therapy were evaluated, stand in contrast to those of the VISEP study. The data published in 2007 by Sakr et al. demonstrate a significant correlation between sepsis, cardiac failure and malign blood diseases and the need for renal replacement therapy, but there was no evidence of an association with the use of HES preparations. 47 A further important difference compared to the VISEP study was the markedly lower accumulated dose of hydroxyethyl starch administered. In an animal study recently conducted by Simon et al. which compared the effect of 6% HES 130/0.42, 10% HES 200/0.5 and 4% gelatin solution with Ringer's acetate solution in a porcine two hit model, a significant deterioration in kidney function and increased damage to the renal tubules were observed with 10% HES 200/0.5 but not with 6% HES 130/0.42 and Ringer's acetate solution. 14 These studies raised concerns in particular directed at the use of high concentration HES solutions (10%) with a molecular weight of 200 kda and above and a degree of substitution of 0.5 and greater. The question still being unresolved in all the studies is whether the HES-induced kidney damage in sepsis is dependent upon the concentration or the molecular weight of the HES solution used. Furthermore, in addition to the composition of the HES preparation used, the cumulative dose of hydroxyethyl starch also seems to be a key factor for the occurrence of disorders of renal function in sepsis. In the meantime, older HES solutions have been replaced by modern third-generation HES for clinical use. These tetrastarches have a molecular weight of 130 kda and a degree of substitution of It has been reported that these tetrastarches have an improved safety profile without loss of effect on volume compared to first- and second-generation HES preparations due to their lower accumulation and more rapid elimination. 48 Large meta-analyses have come to the conclusion that there is no evidence of any difference in terms of safety between the individual HES preparations and that more data are required from clinical trials to demonstrate the superiority of any one preparation. 49,50 In recent years, the results of some large clinical trials have been at some variance; so the safety of 6% HES 130/0.4 in sepsis is once more a matter for current debate. On the one hand Müller et al. evaluated the data of a French multi-centre study in terms of the factors associated with the occurrence of disorders of renal function in patients with severe sepsis and in septic shock. They found that the use of 6% HES 130/0.4 was not associated with renal dysfunction or the need for renal replacement therapy. 51 In the CRYSTMAS study, in which the efficacy and safety of 6% HES 130/0.4 were compared to those of sodium chloride 0.9% as part of haemodynamic stabilisation of patients with severe sepsis, volume therapy with 6% HES 130/0.4 also had no negative impact on renal function. 52 The discussion about the safety of HES was fuelled by the 6S trial group. They aimed to assess the effect of HES 130/0.42 compared with Ringers acetate on mortality, serious adverse reactions and kidney failure in ICU patients with severe sepsis. Therefore the 6S trial group compared in a multicentre, randomised, blinded, study with concealed allocation of septic patients 1:1 to fluid resuscitation using 6/10

7 6% HES 130/0.42 in Ringers acetate or Ringers acetate up to 33 milliliter.kg -1.day -1. The primary outcome measure was either death or end-stage kidney failure 90 days after randomisation. Secondary outcomes included acute kidney failure, need of dialysis and severe bleeding. The two intervention groups had no statistically significant, clinically relevant differences in the baseline characteristics, e.g. transfusion of blood products and albumin use. At 90 days after randomisation, 202 of the 398 patients (51%) assigned to HES 130/0.42 fulfilled the primary outcome of death or end-stage kidney failure, compared with 173 of the 400 patients (43%) assigned to Ringer s acetate, a relative risk of 1.17 (95% confidence interval , p=0.034). Also 90-day mortality and need of dialysis was higher and days alive without dialysis and days alive and out of hospital were lower in patients in the HES 130/0.42 group compared with those in the Ringer s acetate group. The 6S trial group concluded that patients with severe sepsis who were fluid resuscitated with HES 130/0.42 had higher 90-day mortality and need of dialysis and fewer days alive without dialysis and out of hospital compared with those receiving Ringer s acetate. 53 There are several serious issues that require the results of the 6S trial to be interpreted with caution. However, in order to avoid any risk to patients, the results should be taken into consideration for the current fluid therapy for septic patients, despite the substantial criticisms. In the 6S study there was a considerably higher mortality after 28 days compared to other randomised control trials. In fact, the authors stated The trial results come with some limitations. Because of the pragmatic trial design there were no protocols for hemodynamic diagnostics, monitoring or co-interventions except a suggestion to follow international guidelines. There was a complete lack of necessary definitions and prerequisites for fluid therapy in this study protocol. No defined indication, when fluid therapy should be initiated No flow based haemodynamic monitoring for guidance during fluid administration No defined end point when fluid therapy should be stopped because a predefined end-point has been achieved. In 35% of the HES group acute kidney failure was present at baseline. Acute kidney failure is a known contraindication for the use of HES. A taskforce of the European Society of Intensive Care Medicine issued a statement on volume therapy with colloid infusion solutions at the beginning of 2012 which, inter alia, advised against the use of 6% HES 130/0.4 in septic patients outside clinical trials. 54 In the Australian CHEST trial, a prospective, randomized, double-blind, controlled multi-centre trial, the efficacy and safety of 6% HES 130/0.4 was compared to that of sodium chloride 0.9% in a heterogeneous population of over 7000 ICU patients. Here, too, more patients treated with hydroxyethyl starch required renal replacement therapy. However, in contrast to the results of the Scandinavian study, in this study treatment with hydroxyethyl starch did not result in an increased 90- day fatality rate. 55 Remarkably the use of HES in this study was associated with significantly less cardiovascular failure. The patient population was very heterogeneous, ranging from less severely ill patients who were admitted to ICU for the purpose of improved postoperative monitoring, to severely ill septic patients. Indeed, given the heterogeneous study population an identification of differences in outcome parameters could not be expected. Altogether, the study was unsuitable to evaluate adequately the efficacy of HES. Even more, as time until inclusion to the study averaged 10.9 hours (HES group) and 11.4 hours (sodium chloride group), it is very likely that by the time of inclusion, patients had already been haemodynamically stabilised. Besides, due to the pragmatic study approach, the risk of fluid overdosing can also not be ruled out. 7/10

8 In all three studies, VISEP, 6S and CHEST, patients were included more than 10 hours after the diagnosis of sepsis, hence the majority was already haemodynamically stabilised. In other words, these studies cannot answer the question whether HES is suitable to be used effectively in the initial treatment of septic shock. Finally, the unpublished data of the CRYSTAL trial, presented at the 2nd Paris International Conference on Intensive Care 2012, points to a better 90 day outcome in critically ill patients treated with colloids. Annane et al. compared the impact of different colloids, gelatin, dextran, HES, albumin, and different crystalloids, isotonic and hypertonic sodium chloride solutions, ringers acetate and lactated ringers solution in more than 3000 critical ill patients. One should wait until publication before drawing any conclusions. Summary Even with the results of current studies there is still no answer to the question as to what volume replacement provides optimum treatment for the haemodynamic stabilisation of patients in the early phase of septic shock. It is of utmost importance, that these patients receive a sufficient amount of fluid as soon as possible to treat shock efficiently and successfully. Thus, the right indication and timing are very important in volume therapy. Goal directed therapy and differentiated volume management leads to optimal outcome of critical ill patients. It has been suggested that using colloids in the initial therapy of shock is beneficial, but one needs to stop using colloids once the shock has been corrected. Key learning points One of the therapeutic essentials in critically ill patients is an early, sufficient and goaldirected volume replacement therapy. Adequate flow based haemodynamic monitoring should be used to assist appropriate goaldirected volume therapy. We suggest the use of balanced solutions as volume replacement to avoid disturbances of acid-base balance. Based on the results of the 6S trial, there are currently safety concerns regarding the use of HES in septic patients. A summary of the data should be included in the production of high quality guidelines on fluid resuscitation in the not too distant future in Germany in order to provide evidence based recommendations ( 8/10

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