Oxygen dynamics and induced hypothermia in sepsis

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Resuscitation 28 (1994) 65-70

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Oxygen dynamics and induced hypothermia in sepsis A. Gilston 20 Hocroft Avenue, London NW2 ZEH, UK Received 12 January 1994; revision accepted 17 April 1994

The vital distinction between induced and spontaneous hypothermia [l] is highlighted by Villar and Slutsky’s study of moribund septic patients with adult respiratory distress syndrome (ARDS) [2]. The favourable impact of induced hypothermia in this series raises intriguing questions. What factor(s) were responsible for this outcome and why was there no reduction in total oxygen consumption (Vo, rota,)with the fall in temperature, in contrast to another encouraging report [3]? If we accept oxygen imbalance (02 imbalance) (hypoxia) as a major, though not the only factor [4,5] in the development of multiple organ dysfunction and finally multiple organ failure, we can reasonably postulate improved vital organ O2 balance, and hence improved vital organ function, as one major benefit of induced hypothermia. But this improved O2 balance may not have been accompanied by a fall in VO, total for at least two and even three possible reasons. The most attractive explanation lies in the concept of oxygen supply dependency (Fig. 1) and its consequence, tissue hypoxia. This condition was very likely present in these critically ill patients [2], septic shock and metabolic acidosis being two of the criteria for their inclusion in the study. Schumacker et al. [6] have shown experimentally

t

40°C 34°C Co2

*I *hO* Fig. 1.Physiological oxygen supply dependency. Empty circles represent critical 02 delivery for 40°C (00, Crit 4) and for 34°C (Qo2 Crif+,) in this example of a septic patient treated with hypothermia, and (lowest curve) for a normal person at rest. The empty rectangle represents the normal range of resting values. Even when 0, demand is reduced with hypothermia to 34OC, 00, cri, 34 remains above normal. Since Qo, ,o,al (solid circle) is even below Qo, Crits4 he, remains physiologically supply dependant and hypoxic, and Voz rOtalstays unchanged (Fig. 2). A fall in Qo, rotrrtaggravates the problem if there is no compensatory rise in 02ERi,,,l. Any defect in O2 extraction shifts the Qoz crii values to the right and eventually to pathological supply dependency (Fig.3)

0300-9572/94/$07.00 0 1994 Elsevier Science Ireland Ltd. All rights reserved SSDI 0300-9572(94)00763-6

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that the critical value for 02 delivery (Qo, ,-riJ, the anerobic threshold, is normally temperature dependant, rising with pyrexia and falling with hypothermia. It seems possible that in this series [2], total delivery (Qo, totat) was not only below Qo, critfor pyrexia but even below its value for induced hypothermia (Fig. 1). Hence these patients remained supply dependant even when cooled, and O2 demand, though reduced by hypothermia, still exceeded Q% total,but with a now reduced disparity between the two and a reduced total O2 debt (Fig. 2). Vital organ function steadily rose with the improvement in O2 balance, the degree of hypoxia falling as the patient recovered and repaid the O2 debt. The impact of induced hypothermia on pathological oxygen supply dependency (Fig. 3) is unknown and even the existence of this condition is still disputed [7]. Current evidence suggests it may, at least in part, reflect maldistribution, with a pro-

+

02 debt -

02 delivery

O2 consumption

Global 02 demand B

4 Global 02 demand D Fig. 2. Diagrammatic explanation for an unchanged ?o, total in a septic patient despite induced hypothermia. The upper diagram represents the situation at 40°C. Qo~ ,otiltis insuffkient for 0, demand and can satisfy only some of the 0, receptors, the unsatisfied receptors and shaded area representing the O2 debt. Lower diagram, the situation at 34°C. Despite the fall in O2 demand, and no change in Qoz ,otal, there are still unsatisfied 02 receptors. 0, debt falls but since all available 0, is already consumed through maximal 0, extraction, Voz ,Ofal remains unchanged.

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602 Fig. 3. Pathological oxygen supply dependency. The hatched curve and rectangle represent the normal situation and range of resting values. The solid line illustrates the severe defect in 0, extraction which characterizes this condition. The solid circle represents the Vo2 total value for both 41°C and 34°C. As with physiological supply dependency, 0, demand remains unsatisfied despite the fall in temperature and there is no fall in Vo, rota,(see Fig. 2). Any fall in Qo, ,O,alaggravates the problem, and in this condition 02ERtot., cannot rise to compensate.

found mismatch between tissue O2 demand and tissue blood flow. It may have been present in Villar and Slutsky’s patients in view of their inappropriately low 0, extraction (OzER) values, and it too could account for the unchanged VO, totat since O2 balance is unattainable in this condition. A second explanation again depends on a reduction in O2 demand with hypothermia but also on regional changes in Qo2 with this technique. There may be some correction of the inappropriate blood flow pattern which characterizes septic shock [8-111, with flow redistribution from nonvital to vital areas, as with alpha-sympathomimetic agents. Cold-induced cutaneous and maybe muscle vasoconstriction could be part of this effect, though its degree may not be related to the systemic vascular resistance, which can remain virtually unchanged [ 121, perhaps because of matching vasodilatation in other areas. This ‘oxygen switch’ hypothesis for an unchanged VO, total suggests that the rise in VOWin hypoxic vital organs, with an unsatisfied high, though now hypothermia-reduced demand, an exhausted or restricted O2 extraction reserve, and an O2 debt, exactly matches the fall in VO, in non-hypoxic, non-vital tissues, with a lowered O2 demand, a

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high O2 extraction reserve and no O2 debt. In this situation there also would be no change in OzERtotal. Even a fall in VO, ,otal with hypothermia does not necessarily indicate a reduction in total O2 demand and improvement in total O2 balance. It can also signify aggravation of hypoxia from the fall in cardiac output which can accompany hypothermia [2,3], though the effect of hypothermia on the oxyhemoglobin dissociation curve [ 131 does not prevent some compensatory increase in total O2 extraction (02ERtotaJ [2,3]. However in these critically ill patients, and especially those who die in septic shock [14], 02ERtotal is not only severely limited, [15-171 remaining within normal limits (0.22-0.32) despite evidence of hypoxia, including lactic acidosis, but the already detiressed O2 extraction reserve may have been depleted even before hypothermia by the fall in Qo2 totalwith positive end expiratory pressure (PEEP) [ 18,191. The fall in Vo2 total with induced hypothermia does reflect improvement in total O2 balance when it is accompanied by a fall in serum lactate, as in one series [12]. Villar and Slutsky [2] do not report on this parameter. Unfortunately serum lactate has grave limitations as an index of total tissue O2 balance and O2 debt, and the significance of its presence or absence with regard to hypoxia is still disputed [20-231. Global values -

Q% total,Vo2 totaland WRtotal - too are crude and uncertain guides to what is happening in individual tissues under the unequal impact of sepsis [24-261 and during hypothermia. Moreover these measurements do not reflect the wide range of constantly changing tissue O2 demand - O2 supply relationships. It is possible that even in septic shock some tissues remain in O2 balance [27] and even within vital organs there may be a complex and constantly changing mosaic of O2 balance situations. Whilst some vital organs might achieve completely satisfactory oxygen balance with induced hypothermia through the combination of reduced O2 demand and increased blood flow from redistribution, the persistence of lactic acidosis, albeit diminished [12], suggests the opposite. Future studies of induced hypothermia should include gastric intramucosal pH monitoring (pHi) [28,29]; since the splanchnic compartment is re-

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sponsible for most of the increase in metabolism and in O2 demand in septic acute respiratory failure [30]. Neither of the above explanations for an unchanged VOWtotal with induced hypothermia [2] namely continuing supply dependency (pathological or physiological), redistribution of blood flow, or a combination of the two, can exclude a third possibility. The normally close relationship between body temperature and metabolic rate [ 13,311, between heat production and heat loss, is markedly deranged in trauma and sepsis [32-341. In septic shock, for example, Vo2 tolal may be almost normal, despite a marked pyrexia, reflecting the combination of a relatively depressed metabolism [34] and even more diminished heat loss. Induced hypothermia might conceivably enhance heat loss without affecting O2 demand and VOW total,mimicking spontaneous hypothermia in severe sepsis, which reflects a failure of heat conservation despite a depressed metabolic response and has a bad prognosis [35]. Such an interpretation does not allow for the additional impact of profound sedation and muscle relaxation on 0, demand if they are introduced at the time of hypothermia, nor does it explain its beneficial effect. Improved heart action, through several factors, including a reduction in total 0, demand and a consequent fall in cardiac output, enhanced myocardial blood flow [36] by redistribution, reversal of sepsis-induced myocardial depression and edema [37,38] by inhibition of the septic process, and abolition of pyrexia [39], may also be a significant benefit of induced hypothermia, not least because by definition heart failure is the ultimate cause of death, whatever events, including aggressive promotion of O2 delivery, precede it. Unlike sympathomimetic agents induced hypothermia reduces rather than increases the O2 demaqd *of the heart and other tissues. Despite its present convenience, O2 dynamics may be too simplistic an approach to beneficial ! changes in metabolism from induced hypothermia in patients with severe sepsis. It equates hypoxia with ischemia and not only ignores their significant differences [40-421 but other important, though less easily monitored effects of changes in tissue blood flow. The distinction between the two

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supports the increasing doubts whether hypoxia per se is the dominant factor in the development of septic multiple organ dysfunction and failure [4,5] and not simply an important marker. Moreover as Villar and Slutsky suggest [2], the beneficial effects of induced hypothermia may be as much related to profound changes in immune mechanisms as to alterations in global and regional hemodynamics, however intimate the relationship between the two. Perhaps the fall in temperature diminishes the uncontrolled, self-destructive inflammatory response which in the worst cases inexorably leads to a fatal outcome, ‘septic suicide’. Panendothelial damage, including lymphatic dysfunction [43] is not only a characteristic feature of severe sepsis, and one of the manifestations of widespread tissue injury, but it is a central factor in the pathogenesis of septic shock [44]. Recently a patient with severe sepsis and ARDS associated with a Staphylococcus aureus bacteremia showed a very obvious increase in peripheral edema, and a fall in the P,o,/F,o, ratio, when we prematurely allowed his temperature to rise following induced hypothermia. This finding suggests that one of the benefits of the technique is a diminution in the septic assault on endothelium [45] with reduction in capillary leakage, tissue edema and lymphatic overload [46]. It can also explain the rise in arterial oxygenation [2,47], the reduction in the ‘quantity’ of shunt [48] from improved alveolar ventilation more than outweighing the deterioration in mixed venous oxygen content, ‘quality’ of shunt, from the fall in cardiac output and enhanced 02ERtolai. Even normally oxygen diffusion is the limiting factor in tissue oxygen uptake [ 191 and the low tissue oxygen profile and inappropriate low 02ERtotal in septic shock, may be as much due to tissue edema [19,49], and blood flow maldistributions as to increased 0, demand [ 191. The reduction in capillary leak with hypothermia should lead to a fall in urinary albumin since this rises in severe sepsis 1501.

Villar and Slutsky’s report [2] justifies further trials of induced hypothermia in severe sepsis and septic shock with ARDS. It suggests that in selected patients the benefits of pyrexia itself, which are still uncertain [51-531 may be outweighed by the gains from a fall in temperature. It is conceivable that, as is often the case with treatment in

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medicine, induced hypothermia might be even more effective were it used at an earlier stage, rather than as a last resort. At present we have no clear idea of when to use it, its mode of action, or how to judge the optimum fall in temperature, though experience suggests it can gradually be discontinued once there is sustained and progressive improvement, and no relapse with rewarming [47,54]. A combination of mechanical circulatory support [55], induced hypothermia and, assuming pharmacological progress, aggressive use of tissuespecific vasoactive agents in severe sepsis is a possibility for the future. I

Gilston, A. Induced hypothermia Med 1993; 21: 1247-1248.

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