Advances in the Hemodynamic Therapy of Septic Shock
Special Feature
Advances in the Hemodynamic Therapy of Septic Shock
By Francisco Baigorri, MD, PhD
There have been significant advances in our knowledge of the pathogenesis of sepsis and septic shock in the last few years. The concept has emerged that the host’s inflammatory response contributes substantially to the development of septic shock and organ failure.1 Both exogenous mediators, such as endotoxin, and endogenous cytokines have been implicated in this inflammatory response. The most widely investigated cytokines are tumor necrosis factor (TNF), interleukin-1, and interleukin-8, which are generally pro-inflammatory, and interleukin-6 and interleukin-10, which tend to be anti-inflammatory (see Figure). TNF and interleukin-1 promote endothelial cell-leukocyte adhesion, release of proteases and arachidonate metabolites, and activation of clotting. Nitric oxide has also been implicated in the pathophysiology of the cardiovascular response to sepsis. This complex immunologic cascade causes hemodynamic changes that may be detrimental to the host. There is depression of cardiac function, a mixture of vasoconstriction and vasodilation, capillary blockage by cellular and protein material, and capillary leak.2 These changes lead to a maldistribution of blood flow with altered organ perfusion and organ failure.3 Moreover, there has been remarkable progress in our understanding of the cellular injury from subsequent reperfusion and the role of oxygen-free radicals in these circumstances.4
In this decade, we have also learned about the limitations of changes in oxygen delivery (DO2) and oxygen consumption (VO2) values extrapolated from pulmonary artery (Swan-Ganz) catheter measurements of global hemodynamics to detect occult tissue hypoxia.5 Finally, it has been a "rediscovery" of the significance of blood pressure as an important determinant of regional perfusion and to avoid organ dysfunction.6,7 This brief essay discusses recent investigations into the therapy of septic shock in the light of these events.
Modification of Defense Mechanisms
Immunomodulators—Experimental observations prompted large-scale, randomized clinical trials with a variety of immunomodulators such as glucocorticoids, ibuprofen, anti-endotoxin monoclonal antibodies, antagonists of platelet-activating factor, bradykinin-1 or interleukin-1 receptor, and monoclonal anti-TNF antibodies or soluble dimeric TNF receptor fusion proteins. Individually, each of these studies failed to show clinical benefit. There are several possible reasons for these disappointing results. Septic shock patients are too diverse, with differences in comorbidity, severity of illness, types of infecting pathogens, and sources of infection. Conventional management is variable and uncontrolled. It has even been argued that clinical investigation is premature, given the extreme complexity of the inflammation cascade and the present-day limitations in our understanding of the underlying fundamental biology.
A meta-analysis of pooled data from 20 trials testing nonglucocorticoid, mediator-specific agents provides another perspective to assess the value of these agents (see Table).8 The nonglucocorticoid mediator-specific agents produced a small but significant beneficial effect on mortality: the treatment group had a mortality rate of 38%, while the control group had a mortality rate of about 41% (P = 0.04).8 To demonstrate such a modest benefit, a clinical trial would have to enroll 6000-7000 septic patients. For drugs that cost, say, $4000-$5000 per dose, the question raised is whether the price of therapy per patient saved may turn out to be prohibitive in today’s cost-conscious health care environment.
| Table-Mortality Rates in Clinical Trials of Nonglucocorticoid Mediator-Specific Anti-Inflammatory Agents (modified from Reference 8) | ||||
| Agent | No. of Studies | No. of Patients | Mortality (%) | |
| Control group | Treatment group | |||
| Interleukin-1 receptor antagonist | 3 |
1898 |
35 |
31 |
| Bradykinin antagonist | 2 |
755 |
36 |
39 |
| Platelet-activating factor antagonist | 2 |
870 |
50 |
45 |
| Anti-TNF monoclonal antibodies | 8 |
4130 |
42 |
39 |
| Soluble TNF receptors | 2 |
639 |
37 |
40 |
| Prostaglandin antagonist: ibuprofen | 3 |
514 |
40 |
38 |
| All studies | 20 |
8806 |
41 |
38 |
The use of glucocorticoids in septic shock deserves special consideration. Clinical trials of high-dose glucocorticoids indicate a trend toward a harmful effect.8 However, in recent years, several authors have hypothesized a syndrome of relative adrenocortical insufficiency in septic shock in the presence of normal or even elevated serum cortisol concentrations. Moreover, a few uncontrolled studies indicate that stress doses of hydrocortisone improve hemodynamics in patients with hyperdynamic septic shock unresponsive to conventional therapy. The data of recent double-blind studies suggest that moderate doses of glucocorticoids given as a prolonged treatment contribute to control the systemic inflammatory response.9,10 Further investigation should elucidate this inexpensive approach to immunomodulation.
Nitric oxide synthase (NOS) inhibitors have also been tested in patients with septic shock. The administration of NG-methyl-L-arginine (L-NMA, 546C88), the most widely used nonselective NOS inhibitor, is associated with an increase in peripheral vascular tone and a fall in cardiac index. Preliminary results of the phase III prospective, randomized, double-blind, placebo-controlled trial of 546C88 have been recently reported.11 Unfortunately, the study had to be discontinued due to increased mortality in the group treated with 546C88.11
Hemofiltration—Another approach to the management of septic shock may be to remove inflammatory mediators by extracorporeal methods. Various forms of hemofiltration have been investigated. There is evidence that high-volume hemofiltration/hemodiafiltration with a large-pore membrane is able to improve the left ventricular systolic function in septic shock. However, the mechanism by which hemofiltration acts is not as simple as was previously expected. The critical review of existing literature on cytokine removal with renal replacement therapy leads to the conclusion that their characteristics are not compatible with clinical relevant removal. It is possible that hemofiltration removes some other mediators, such as arachidonic acid metabolites, beta-endorphin, bradykinin, or complement factors, but their role in sepsis-induced left ventricular dysfunction seems weak.
Thus, the effects of hemofiltration on left ventricular function may be explained by its ability to remove water from plasma or by changes in plasma osmolarity. In addition, other metabolic events, such as hypothermia, altered glucose concentration, or acidosis correction, may play a more important role in myocardial function improvement in sepsis than any mediator removal.12 The question of whether this technique should be used in patients with septic shock before the appearence of renal failure remains unanswered.
Supernormal Oxygen Delivery
Studies using independent methods to determine systemic oxygen delivery (DO2) and oxygen consumption (VO2) have not found pathologic dependency of the latter on the former in septic patients. Nevertheless, although pathologic dependence of VO2 on DO2 has not been confirmed using a whole-body approach, we cannot be sure that the VO2 of individual organs behaves in a parallel manner with whole-body VO2. In addition, it has been observed repeatedly that critically ill patients who survive usually have higher values of cardiac output, DO2, and VO2 than those who do not survive. Consequently, supranormal values of cardiac output and DO2 may be proposed as targets of resuscitation trying to correct occult tissue hypoxia.
Several randomized control trials of supernormal compared with normal DO2 in critically ill patients have been carried out. A systematic review of the current data was published recently.13 Heyland and colleagues cited seven studies involving 1016 patients. They found that interventions designed to achieve supraphysiologic goals of cardiac index, DO2, and VO2 did not significantly reduce mortality rates in all critically ill patients, but concluded that methodologic limitations prevented making any general conclusion. On the other hand, the maintenance of DO2 at supranormal levels in all patients could result in overzealous administration of fluids and vasoactive agents, with evident hazardous effects.14 Thus, current evidence does not support values of cardiac output and DO2 as targets of resuscitation in patients with sepsis, shock, or trauma, other than those able to correct hypotension and signs usually associated with inadequate tissue perfusion, such as metabolic acidosis, elevated blood lactate levels, abnormal mentation, and low urine output.15
The quest continues for better methods for identifying dysoxia that provide not only systemic but also regional data for individual vital organ systems. In this respect, tonometry can uncover regional hypoxia and hypoperfusion involving the gut. However, it is increasingly evident that intracellular metabolic derangements also contribute to defects in adenosine triphosphate synthesis and accelerated anaerobic metabolism in sepsis.16 However, elevated tissue PCO2 values are not incontrovertible evidence of inadequate microvascular perfusion in sepsis.17
Blood Pressure
Blood pressure is an important determinant of regional perfusion, particularly in the presence of ischemia when conductance is at a nadir. Normal mean arterial pressure is in the range 80-100 mmHg. However, mean arterial pressure necessary to maintain urine output in septic patients may frequently need to be much higher than this. Then, the end points of circulatory resuscitation are the provision of an adequate systemic DO2 and perfusion pressure. The first step is to restore and maintain circulating blood volume and then restore interstitial fluid volume. Nevertheless, volume resuscitation alone, and perhaps administration of inotropes, is often insufficient to adequately augment blood pressure, and vasopressor drugs are required.18
Although vasopressor catecholamines may theoretically reduce tissue perfusion through their vasoconstrictor action, this deleterious effect may be offset by a rise in blood pressure, provided adequate volume expansion and systemic DO2. In this respect, norepinephrine seems to be more efficient and reliable than dopamine to reverse the hemodynamic abnormalities seen in hyperdynamic septic shock.19 A number of studies in patients with septic shock support this notion by showing that norepinephrine infusion is associated with an increase in urine flow and creatinine clearance.
Another important concern is whether norepinephrine could reduce splanchnic bed perfusion. But norepinephrine administration in septic shock patients has been associated with an increase in VO2 and a reduction of blood lactate levels, suggesting correction of splanchnic ischemia with an efficient hepatic lactate uptake. Moreover, it has also been shown that norepinephrine, compared to high-dose dopamine, increased gastric intramucosal pH.20
Whether using norepinephrine in sepic shock patients affects mortality, as compared to the use of dopamine or epinephrine, still requires a prospective clinical trial. This notwithstanding, reported overall survival in patients with septic shock treated with norepinephrine when volume and dopamine therapy has failed to increase blood pressure is approximately 40%, a substantial survival for such a critically ill patient group. In our clinical experience, norepinephrine has been increasingly used and started earlier in the course of septic shock. In the 1950s Dr. Moyer indicated in the first publication on the use of norepinephrine in septic shock: "When the use of this drug is contemplated, it should be used as early as possible in order to prevent damage of the brain, kidney, liver and other vital organs. It should not be withheld as a last resort."21
Conclusion
Over the last decade, our understanding of the biochemistry of sepsis has improved dramatically. This knowledge has led to test novel immunomodulating agents in the management of sepsis. Unfortunately, the efficacy of these drugs in lowering the mortality rate among critically ill patients with sepsis remains unproved. New anti-inflammatory agents continue to be tested. In the meantime, the treatment of septic shock continues to focus on eradicating infection and supporting failing organs.22 Therapeutic end points of cardiovascular support remain the achievement of those values of blood pressure and DO2 that reverse the evidence of inadequate tissue perfusion. It requires restoration of intravascular volume. However, volume resuscitation alone is often insufficient to adequately augment blood pressure, and vasopressor drugs are required without delay.
References
1. Parker MM. Pathophysiology of cardiovascular dysfunction in septic shock. New Horiz 1998;6:130-138.
2. Hinshaw LB. Sepsis/septic shock: Participation of the microcirculation: An abbreviated review. Crit Care Med 1996;24:1072-1078.
3. West MA, Wilson C. Hypoxic alterations in cellular signal transduction in shock and sepsis. New Horiz 1996;4:168-178.
4. Ar’Rajab A, et al. Reperfusion injury. New Horiz 1996; 4:224-234.
5. Baigorri F, Russell JA. Oxygen delivery in critical illness. Crit Care Clin 1996;12:971-993.
6. Bersten AD. In defense of blood pressure. In: Vincent JL, ed. Yearbook of Intensive Care and Emergency Medicine. Berlin: Springer, 1995.
7. Bersten AD, Holt AW. Vasoactive drugs and the importance of renal perfusion pressure. New Horiz 1995;3:650-661.
8. Natanson C. Reevaluation of anti-inflammatory trials in sepsis: A meta-analysis. In: Nelson S, ed. Cytokines and pulmonary infection. Part II: The role of cytokines in systemic and pulmonary medicine. New York: American Thoracic Society, 1997:7-18.
9. Bollaert PE, et al. Reversal of late septic shock with supraphysiologic doses of hydrocortisone. Crit Care Med 1998;26:645-650.
10. Briegel J, et al. Stress doses of hydrocortisone reverse hyperdynamic septic shock: A prospective, randomized, double-blind, single-center study. Crit Care Med 1999;27:723-732.
11. Grover R, et al. Multi-center, randomized, placebo-controlled, double blind study of the nitric oxide inhibitor 546C88: Effect on survival in patients with septic shock. Crit Care Med 1999;27(Suppl. 1):A33.
12. Dhainaut JF, et al. Hemofiltration and left ventricular function in sepsis: Mechanisms and clinical implications. Crit Care Med 1999;27:473-474.
13. Heyland DK, et al. Maximizing oxygen delivery in critically ill patients: A methodologic appraisal of the evidence. Crit Care Med 1996;24:517-524.
14. Hayes MA, et al. Elevation of systemic oxygen delivery in the treatment of critically ill patients. N Engl J Med 1994;330:1717-1722.
15. Third European Consensus Conference in Intensive Care Medicine. Tissue hypoxia. Am J Respir Crit Care Med 1996;154:1573-1578.
16. Van der Meer TJ, et al. Endotoxemia causes ileal mucosal acidosis in the absence of mucosal hypoxia in a normodynamic porcine model of septic shock. Crit Care Med 1995;23:1217-1226.
17. Fink MP. Tissue capnometry as a monitoring strategy for critically ill patients. Just about ready for prime time. Chest 1998;114:667-670.
18. Nightingale P, Beards SC. Tissue hypoxia: How to correct? Objectives and strategy. Réan Urg 1996;5(2 bis):267-273.
19. Martin C, et al. Norepinephrine or dopamine for the treatment of hyperdynamic septic shock? Chest 1993; 103:1826-1831.
20. Martin C. Why, when and how I use norepinephrine in the treatment of septic shock. In: Vincent JL, ed. Yearbook of Intensive Care and Emergency Medicine. Berlin: Springer, 1999:175-188.
21. Moyer J, et al. Norepinephrine: Effect in normal subjects; use in treatment of shock unresponsive to other measure. Am J Med 1953;15:330-343.
22. Wheeler AP, Bernard GR. Treating patients with severe sepsis. N Engl J Med 1999;340:207-214.
Which of the following seems to be useful to treat patients with septic shock?
a. Hemofiltration used even with normal renal function.
b. High doses of glucocorticoids.
c. Supranormal DO2 levels in all patients.
d. Vasopressors used to adequately augment blood pressure provided an adequate volume expansion and systemic DO2.
e. Treatment with nitric oxyde synthase inhibitors.
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