Pulmonary edema and blood volume after aneurysmal subarachnoid hemorrhage: a prospective observational study

Pulmonary edema (PED) is a severe complication in patients with a subarachnoid hemorrhage (SAH) from rupture of an intracranial aneurysm [1, 2]. PED can result in severe hypoxemia and thus contribute to cerebral hypoxia in a brain that is already vulnerable to secondary injury. PED thereby increases the risk of poor outcome [2, 3]. Next to such well-known causes of PED as cardiac failure or inflammatory reactions in the pulmonary tissue (for example, in sepsis), PED after SAH can have a neurogenic origin. Neurogenic PED is defined as an increase in interstitial and alveolar lung fluid occurring as a direct consequence of an acute central nervous system injury.

In the pathophysiology of neurogenic PED, several mechanisms are involved [1, 4]. An abrupt increase in intracranial pressure or a localized ischemic insult in so-called neurogenic PED trigger zones, in the hypothalamus and medulla oblongata, leads to a massive sympathetic discharge. Severe systemic and pulmonary vasoconstriction ensues, with systemic hypertension and a marked increase in pulmonary hydrostatic pressure. This is followed by a fluid shift from the pulmonary capillaries into the lung tissue. Furthermore, the cerebral insult leads to inflammatory responses in the brain, with an increase in the production of brain cytokines, which can trigger inflammatory processes outside the brain. A systemic inflammatory response is accompanied by capillary leakage and the formation of generalized and pulmonary edema. The supraphysiologic sympathetic stimulation may also provoke cardiac dysfunctions with rhythm and conduction disturbances and mechanical pump failure, which contribute to the formation of PED.

Management of PED after SAH is centered on the traditional treatment strategies for cardiac failure-induced pulmonary edema, such as a reduction in preload and afterload and the use of inotropics [1, 4, 5]. A reduction in preload, by administration of diuretics and by a reduction in fluid intake, carries a risk of intravascular volume depletion. Patients after SAH already have a high risk of hypovolemia, and hypovolemia is associated with delayed cerebral ischemia and with poor outcome [6, 7]. The avoidance of hypovolemia by ample fluid intake and, in some cases, the induction of hypervolemia, is therefore a mainstay of treatment after SAH [8]. To guide fluid management adequately, an accurate knowledge of volume status is required.

We assessed intravascular volume in patients after SAH and compared it between patients in whom PED did or did not develop.

Our results show that PED after SAH is accompanied by a strong decrease in blood volume. Patients with PED had a mean blood volume in the hypovolemic range in the days preceding the diagnosis of PED. Patients in whom PED developed more often had diuretics prescribed by the treating physicians in the days before the diagnosis of PED was made. Cardiac index tended to be somewhat lower and fluid balance somewhat more positive in patients with PED, but these differences were no longer statistically significant after adjusting for age, weight, and clinical condition. Calculations were based on measurements obtained in the time period from the day after SAH until the day PED was diagnosed, so these results were not influenced by any therapeutic measures initiated by the treating physicians to counteract PED.

We were unable to find any previous studies in which blood volume was actually measured in PED patients, either in patients with a cardiac origin of the edema (by systolic or diastolic pump failure), or in patients with noncardiogenic edema (by increased pulmonary capillary permeability). Central venous pressure and pulmonary capillary occlusion pressure are often used in PED to inform about volume status [15]. However, no clear relation exists between these pressures and the presence of neurogenic PED, or between these pressures and measured blood volume [5, 16, 17].

It was previously noticed that neurogenic PED develops earlier in patients with a normal systemic circulating volume, compared with hypovolemic patients [1, 18]. Patients in the Optica intervention group more often had blood volumes in the normovolemic range than did control group patients [9]. The present analysis showed that intervention-group patients tended to be at increased risk of PED and that patients in the intervention group developing PED tended to have a more positive fluid balance and a higher (but still reduced) mean blood volume. Interpretation of these differences must be made with caution because of the small number of patients in this comparison. However, this might indicate that measures to prevent hypovolemia after SAH lead to an increased risk of PED.

The cardiac index was slightly (nonsignificantly) lower in patients with PED than in those without, but not to such an extent as to indicate cardiac failure. This suggests that PED in our study did not have a cardiogenic origin, but was likely neurogenic or part of a systematic inflammatory response syndrome (SIRS). The reduced blood volume we found in patients with PED also suggests a noncardiogenic cause. A reduction in cardiac index could be explained by the cardiac dysfunction often accompanying neurogenic PED. Alternatively, preexisting hypovolemia may have led to a decrease in cardiac filling and thereby to a reduction in cardiac index. Because we did not perform serial echocardiography, we were unable to make this distinction.

The reduction in blood volume we observed in patients with PED after SAH does not necessary imply a causal relation. Patients in whom PED developed were older and more often admitted in a poor clinical condition, which is in agreement with previous studies [4]. Ill patients tend to develop more signs of SIRS, with capillary leakage and the formation of a generalized edema [19]. This loss of fluid from the circulation reduces blood volume. Fluid retention is the usual reaction of the body to a reduction in volume status, thereby leading to a more-positive fluid balance. Both the presence of generalized edema and a positive fluid balance could erroneously be interpreted as a sign of fluid overload in a patient with SIRS. This could trigger the treating physicians to deviate from the fluid-management protocol and to use diuretics. A previous study found no association between the fluid balance and actual measured blood volume [20]. In our present study, diuretics were used far more often in patients in whom, in later days, PED developed than in patients without edema. We did not collect information on the motives for the use of diuretics. However, the use of diuretics in patients with already impending hypovolemia may have played an important role in the reduction in intravascular volume that we observed.

Furthermore, any formation of PED implies a fluid shift from the vascular system to the lung tissue. Therefore, the occurrence of PED could contribute to a further reduction in blood volume.

A limitation of our study is that the diagnosis of PED was based on clinical criteria in combination with chest radiograph findings. The physicians responsible for patient care were not blinded for treatment allocation. This may have contributed to an increase of PED diagnosed in the intervention group, because some clinicians believed that patients in the intervention group were at increased risk for hypervolemia and pulmonary edema. We did not categorize the severity of edema. Less-severe instances of pulmonary edema may have escaped detection, as extravascular lung water must increase by >30% for edema to be visible on a chest radiograph [15]. We did not routinely monitor central venous pressure or pulmonary capillary wedge pressure in these patients, because of the poor relation between these pressures and actual volume status. Another limitation concerns the definition of normal blood volume. Previous studies found "normal" blood volume values in adults of ~70 ml/kg [7, 14]. However, the changes in blood volume that occur as a result of illness or therapy are incompletely understood [21]. For this reason, we used wide margins in our definition of normovolemia (60-80 ml/kg). Even with these large margins, patients developing PED fell outside this range and were considered hypovolemic.

Notably, volume status is only one of the factors determining the adequacy of tissue perfusion. To evaluate the patient's cardiovascular status, many hemodynamic parameters must be taken into consideration together and seen in the context of the overall clinical condition.

Patients with PED after SAH must be considered hypovolemic and therefore at increased risk of delayed cerebral ischemia. This renders fluid management in these patients especially difficult. Measures aimed at relieving pulmonary congestion and improving oxygenation (for example, preload reduction) might increase hypovolemia, whereas measures to improve volume status might worsen pulmonary edema and possible hypoxemia. Both hypovolemia and hypoxemia are extremely deleterious for the recently injured brain. To balance these potentially conflicting goals, clinicians might consider refraining from measures that reduce preload and instead use early (noninvasive) positive-pressure ventilation to maintain oxygenation. This might allow administration of additional fluid to maintain normovolemia without a further decrease in arterial oxygen saturation. The effects of such a treatment policy on circulation, ventilation, and neurologic outcome must be formally studied.

RGH is an anesthesiologist-intensivist at the UMC Utrecht, the Netherlands. GJER is a professor in neurology at the UMC Utrecht, the Netherlands. BHV is a neurosurgeon at the UMC Utrecht, the Netherlands. CJK is a professor in anesthesiology at the UMC Utrecht, the Netherlands. AA is a professor in clinical epidemiology at the UMC Utrecht, the Netherlands.