Relationships between dopamine infusions and intracranial hemodynamics in patients with raised intracranial pressure

Clinical Nrzfrdogy 0

CLINEU

143

and ~~ur~.~l~~~~r~, 94 (1992) 143-148

1992 Elsevier Science Pubfishers

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ODOR-~467~92/$05.00

00185

Relationships between dopamine infusions and intracranial hemodynamics in patients with raised intracranial pressure R. Nau, D. Sander and J. Klingelh6fer

(Received (Revised,

(Accepted

Key lords:

22 March,

received

1991)

29 November

29 November,

199 1)

1991)

Dopamine; Brain edema; Intracranial pressure; Transcranial Doppler ultrasonography

Summary Dopamine, I-10 pug/kg body weight/min was infused in 6 patients suffering from cerebrovascular diseases with elevated intracranial pressure and a critical cerebral perfusion pressure. Dopamine decreased intracranial pressure in 3 and increased it moderately in the other 3 patients. In all patients, the dopamine-induced rise of mean arterial pressure led to an increase of cerebral perfusion pressure. Transcranial Doppler ultrasonographic recordings of the middle cerebral artery in patients whose intracranial pressure declined revealed a decrease of the pathologically elevated cerebrovascular resistance, and an augmentation of cerebral blood supply. In conclusion, dopamine infusions may improve cerebral hemodynamics in some patients with severe brain edema. Such patients can be identified by intracranial pressure and Doppler monitoring.

A sufficient cerebral perfusion pressure (CPP) is essential for an adequate blood supply of the brain. Under physiological conditions, the intrinsic cerebral autoregulatory mechanisms are able to maintain cerebral blood flow (CBF) constant between a CPP of 50-150 mm Hg [l-3]. Severe head injury, however, is often accompanied by an impaired autoregulatory capacity [4-91; any reduction of CPP in these cases diminishes CBF with the risk of development of secondary ischemic deficits [IO-121. Under these circumstances, a CPP of 40-50 mm Hg is

Correspondence nical University Abbreviations: sion pressure; pressure; tension;

to: J. Klingelhbfer. of Munich,

Mohlstr.

CBF, cerebral ICP. mean

trasonography.

of Neurology,

artery;

resistance;

pressure;

MAP, mean

p.COz, arterial TCD, transcranial

Tech-

80, F.R.G.

blood flow; CPP, mean cerebral

intracranial

MCA, middle cerebral R, cerebrovascular

Department

28. W-8000 Munchen

carbon

perfuarterial dioxide

Doppler

ul-

considered as the critical minimum for adequate cerebral perfusion. As CPP represents the difference between mean arterial pressure (MAP) and mean intracranial pressure (ICP), low MAP as well as elevated ICP can cause an insufficient CPP. Improvement of CPP may be achieved either by lowering ICP or by increasing MAP. Dopamine is widely used in intensive care to increase blood pressure and cardiac output and to counterbalance the adverse effects of continuous positive pressure ventilation [13-l 51. Dopamine exerts its effects via stimulation of adrenergic, alpha- and beta-receptors and via specific dopamine receptors [16]. In animal experiments, in the absence of elevated ICP it has been shown that CBF decreases in response to intravenous infusion of dopamine at low rates (~2 pugikglmin), increases in response to moderate rates (2-6 pug/kg/h) and again decreases in response to high infusion rates (7-20 ,ug/kglh) [17,18]. The aim of the present study was to assess whether

144 and stored on magnetic tape together with the simultaneously recorded ICP and blood pressure curves during the whole phase of dopamine infusion. The index of cerebral circulatory resistance (R) introduced by Pourcelot [22] was calculated from the recorded MCA flow patterns as: R = (maximum systolic flow velocity - end-diastolic flow velocity) / maximum systolic flow velocity. Standard therapy of elevated ICP consisted in glycerol 50&100 g/d i.v. continuously, mannitol i.v. after sudden ICP elevations, artificial hyperventiIation (P~CO, approximately 30 mm Hg), and high-dose thiopental [23251. For that reason, the assessment of the neurological status confined itself on pupil width, response to light, and the other brain stem reflexes. Patients with subarachnoid hemorrhage additionally received dexamethasone and nimodipine. Arterial oxygen tension was between 80.3 mm Hg and 144.7 mm Hg resulting in an oxygen saturation of 96.1-99.0%. During the observation period, the ventilation parameters were not changed and no boli of glycerol, other osmodiuretics, or thiopental were given. intravenous dopamine was administered when a patient fulfilled the following criteria: (1) CPP < 50 mm Hg, and (2) ICP B 20 mm Hg. Dopamine was increased by 1 ,ug/kg body weight/min every 5 min up to 10 pglkglmin. To avoid potentially hazardous consequences (especially in the 2 patients with SAH), the dopamine application was not further increased if CPP exceeded 80 mm Hg (patients I, 2) or severe cardiac arrhythmias occurred before reaching 10 ~~kg/min. In patients 3-6, the measurements were started when they already received a low dose of 2 pgikgl min dopamine for several hours. As it was not feasible to

dopamine is able to improve the cerebral perfusion pressure in humans with severe elevated ICP or whether the cerebral vasodilation observed in animal experiments gives rise to dangerous increases in ICP.

Patients and methods Six patients suffering from various cerebrovascular diseases accompanied by severe brain edema were evaluated in this study. The essential data of these 6 patients are summarized in Table 1. ICP was measured with an epidural device [19] (Gaeltee ICTlb) in 5 patients and by means of an external ventriculostomy in one patient. Arterial carbon dioxide tension (p;,CO,) and arterial oxygen pressure (p,O,) were monitored by blood gas analysis. Arterial blood pressure was recorded using a pressure transducer (Gould Statham P 23 ID) in the radial artery. Systolic, diastolic, mean arterial pressure (MAP), and ICP were recorded and stored by a computerized intensive care monitor (Hellige Servomed SMC 108). Measurements of the blood flow velocity of the middle cerebral artery (MCA) of the less impaired cerebral hemisphere were performed with a 2 MHz pulsed transcranial Doppler (TCD) device (EME TC 2-64B) [20]. The Doppler probe was placed between the lateral margin of the orbit and the ear above the zygomatic arch. The sample depth and position of the probe were altered until the trunk of the MCA was insonated and the maximal mean flow velocity could be determined (211. The Doppler probe was then fixed in that position by means of a specially attached probe holder. In 3 patients (nos. 1-3) the flow patterns of the MCA were recorded continuously TABLE 1 CLINICAL

DATA -

Patient No.

Age/sex

1 2 3

56/M 55lM .58/F

4 5 6

47/M 59lM 62/F

Underlying disease

subarachnoid right-hemisph. subarachnoid right-hemisph. right-hemisph. right-hemisph.

hemorrhage infarction hemorrhage infarction infarction infarction

Abbreviations: CMV = controlled mandatory = dexamethasone; T = thiopentai. “Determined before dopamine administration.

ventilation;

Mode of ventilation

CMV. CMV, CMV, CMV, CMV, CMV,

PEEP PEEP PEEP PEEP PEEP PEEP

0 4 cm H,O 5 cm HI0 4 cm H,O 0 0

PEEP = positive endexpiratory

)-IgI

Drug therapy of elevated ICP

30.5 27.3 27.2 27.8 31.6 29.2

G, M. D, T G, M, T G. D, T GMT G, M, T G, M, T

paC02” (mm

pressure; G = glycerol; M = mannitol; D

145

CPP

ICP

[mm&t]

[mmHg]

60-

fm 0

Fig. 2. CPP changes

Dopamlne 1

2

3

4

5

6

7

8

g

10

[pg/kgbody

weight/mm]

Fig. 1. ICP changes during infusion of dopamine in 6 patients with cerebrovascular disease. Dopamine was increased by 1 pg/ kg body weightimin every 5 min up to 10 pglkgimin. No full doseeresponse curves were obtained for reasons described in

the Methods.

stop the dopamine

infusion

during infusion

of dopamine

in 6 patients

with cerebrovascular disease. Dopamine was increased by 1pcgi kg body weightimin every 5 min up to 10 pgikglmin. No full dose-response curves were obtained for reasons described in the Methods.

cause of a rapid fall of MAP or needed

osmotic

for an abrupt increase in ICP were not subjected study protocol for ethical reasons.

under the condition

ically low CPP, a full dose-response-curve

agents to the

of a crit-

could not be

obtained in these patients. For standardization, patients who received another sedation or therapy of elevated

Results

ICP than that outlined above were not included. Patients who immediately required high-dose catecholamines be-

Dopamine in 3 patients

TABLE 2

(nos. 4-6) developed an increase of ICP of less than 10 mm HG. The changes of ICP did not result in alterations of the neurological status. Patients whose ICP rose during dopamine infusion had a higher initial ICP than

RATIO OF MEAN CEREBRAL PERFUSION PRESSURE (CPP) AND MEAN ARTERIAL PRESSURE (MAP) IN 6 PATIENTS BEFORE AND AFTER DOPAMINE INFUSION Patient

No.

those whose ICP decreased fusion. In 2 of the 3 patients rose by more than

Ratio CPPiMAP

in response with decreasing

to dopamine

in-

ICP, the CPP

30 mm Hg. In the patients

with in-

creasing ICP, the increase of mean blood pressure exceeded the rise of ICP, resulting in an elevation of CPP in

Before”

After”

1 2 3

0.67 0.69 0.58

0.65 ? 0.06b

0.82 0.85 0.78

0.82 ? 0.04h

4 5 6

0.62 0.50 0.52

0.55 + 0.06h

0.67 0.58 0.53

0.59 k 0.07’

“Dopamine infusion. ‘Mean ? SD.

displayed different effects on ICP (Fig. 1): (nos. l-3) ICP decreased; three patients

all 6 patients (Fig. 2). To illustrate the different behavior of patients l-3 and 46, the ratio CPPiMAP was calculated. In normal subjects, the coefficient usually lies above 0.8; before dopamine infusion values between 0.50 and 0.69 were registered (Table 2). In patients l-3 dopamine administration clearly increased the CPPiMAP ratio, while in patients 4-6 its rise was minimal (Table 2) suggesting that the MAP increase due to dopamine was neutralized by a concomitant ICP elevation.

146 indicating a decreased peripheral cerebrovascular resistance. In the 2 other patients (nos. 1 and 3) with decreasing ICP in response to dopamine, the same development of the MCA flow patterns was observed: in all 3 cases mean flow velocity increased while R fell suggesting a diminution of peripheral cerebrovascular resistance (Table 3).

Discussion _-

”

-_

2s

25

time lsl

Fig. 3. Simultaneous recording of the left middle cerebral artery (MCA) flow velocity, blood pressure (RR), and intracranial pressure (ICP) before (A) and during (B) infusion of 8 ,uglkgl min dopamine in patient 2. Dopamine caused a rise of blood pressure, a reduction of ICP and a concomitant increase of MCA flow velocity.

Simultaneous TCD recordings were performed in the three patients (nos. 1-3) with decreasing ICP during the administration of dopamine. The other 3 patients were not studied by TCD as the Doppler device was not immediately available and the physician in charge of the patient considered that the dopamine infusion should be started quickly. Figure 3 shows a representative recording. Before dopamine infusion (Fig. 3A) MAP ranged from 65 to 70 mm Hg, ICP from 20 to 25 mm Hg, and CPP from 45 to 50 mm Hg. The adverse effects of this constellation on cerebral perfusion are reflected in the MCA Aow profile: the mean flow velocity was reduced and the cerebrovascular resistance was clearly elevated (R = 0.83). During dopamine infusion ICP decreased to 15 mm Hg and MAP increased to 100 mm Hg (Fig. 3B) with a resulting CPP of 85 mm Hg. As CPP exceeded 80 mm Hg with 8 ,uglkg/min dopamine, the dose was not further increased. The CPP improvement corresponded to a normalisation of the MCA flow patterns (Fig. 3B). The mean flow velocity rose to 52 cm/s, R fell to 0.59 TABLE 3 PERCENTAL CHANGES OF MEAN FLOW VELOCITY (MFV) AND CEREBROVASCULAR RESISTANCE (R) [22] AFTER DOPAMINE INFUSION IN 3 PATIENTS Patient No.

MFV

R

1

+ 22% + 86% + 27%

-11% -29% -15%

2 3

Dopamine administered intravenously has a short plasma half-life of 1-2 min [26]. Similarly, during infusion of 5 ,ug dopamine/kg/min in volunteers and critically ill patients, all reached steady state plasma concentrations within 10 min; 6 min after the beginning of the infusion dopamine plasma concentrations were approx. 75% of the steady state levels [27]. We chose the interval of 5 min between increases of the dopamine infusion rate by 1 ~g/kg/min in order to get close to the steady state levels at the end of the 5 min interval, to minimize effects due to changes in the underlying conditions of elevated ICP and not to withhold patients needing circulatory support by catecholamines from adequate therapy. Two different effects of dopamine administration on the behavior of ICP were observed: in 3 patients with an initial ICP of < 25 mm Hg, dopamine caused a lowering of ICP (group A), while ICP moderately increased in 3 patients whose starting ICP exceeded 30 mm Hg (group B). In spite of the divergent effects on ICP, all patients responded with a rise of CPP; it was more pronounced in group A due to the synergistic effect of MAP increase and ICP decrease. One could argue that the decline of ICP in group A was the result of an active constriction of cerebrovascular resistance vessels due to pressure autoregulation or direct activation of adrenergic-receptors by the infused dopamine [16] and concomitant reduction of blood volume. However, this mechanism probably was not a cause for the observed ICP decrease: (1) since all patients investigated suffered from severe brain edema, an extensive impairment of cerebrovascular autoregulation has to be assumed [4-91. (2) In animal experiments, from 2 to 6ggi kgimin dopamine increased cerebral blood flow, vasoconstriction predominating only at low and high doses [ 17,181. (3) Doppler sonographic assessment of the cerebrovascular resistance [22,28] resulted in a dose-dependent decrease of this parameter over the whole range of dopamine infusion. As cerebrovascular resistance declined, another cause

147 for the ICP decrease in group A has to be discussed: it has been shown that with high ICP the major contribution to cerebrovascular resistance does not originate from the cerebral arterial resistance vessels but from stenosis of the venous pathway at the junction between bridging veins and intradural venous sinuses [29-311. The dopamine-induced elevation of MAP increased the transmural pressure gradient. In the 3 patients of group A (starting ICP < 25 mm Hg) this may have led to a reopening of collapsed parts of the intracranial venous system resulting in a decline of the cerebrovascular outflow resistance [32] and a concomitant reduction of cerebral blood volume and ICP. Consequently, TCD flow profiles of the MCA showed an increase of mean flow velocity and a decrease of cerebrovascular resistance reflecting the decrease of ICP [33,34]. In such patients, application of dopamine is a promising approach to improve cerebral perfusion in severe brain edema with critical CPP. The hypothesis that the ICP fell due to a reopening of collapsed intracranial veins was verified in animal experiments with cannulation of the intracranial venous sinuses and bridging veins [29,30]. This procedure is too invasive to be applied in humans. In patients with an initial ICP of greater than 30 mm Hg (group B) the effect of dopamine infusion was less favourable: the dopamine-induced rise of MAP was accompanied by an increase of ICP probably due to an augmentation of intracranial blood volume [5,6]. Although no deterioration of the neurological status was observed (this remained unchanged during the study period), the ICP increase raises the question as to whether the moderate increase of CPP had a beneficial effect on cerebral perfusion in these patients. As demonstrated by our results, dopamine infusions are potentially able to improve cerebrovascular hemodynamics in critically ill patients with severe brain edema. However, monitoring of ICP is essential to discriminate between those patients who may benefit from the dopamine-induced rise of MAP concomitant with a decrease of ICP, and those for whom such procedure may be of doubtful advantage, as ICP rises in response to the MAP increase. Transcranial Doppler ultrasound recordings of systolic, diastolic, and mean MCA blood flow velocity and calculation of cerebrovascular resistance [22,28] provide valuable additional information about cerebral hemodynamic changes induced by dopamine administration. Using ICP and TCD monitoring, it is possible to define the patients suffering from severe brain insult in which dopamine infusions can be applied to lower ICP and substantially raise CPP. To assess the pos-

sible therapeutic value of dopamine infusions in patients with intracranial hypertension, further animal and clinical studies on metabolic changes and on alteration of the clinical outcome will be necessary. Acknowledgement

This work was supported in part by the Deutsche Forschungsgemeinschaft (SFB 220).

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