Cardiorespiratory effects of continuous i.v. administration of the ACE

Br J Clin Pharmacol 1995; 40: 415-422

Cardiorespiratory effects of continuous i.v. administrationof the ACE inhibitor enalaprilat in the critically ill

JOACHIM BOLDT, MATTHIAS MULLER, MICHAEL HEESEN, KLAUS HARTER & GUNTER HEMPELMANNDepartment of Anaesthesiology and Intensive Care Medicine, Justus-Liebig-University Giessen, 35392 Giessen,Germany

1 Cardiorespiratory effects of long-term, continuous i.v. administration of the ACEinhibitor enalaprilat were studied.

2 Forty-five consecutive critically patients suffering from trauma or postoperativecomplications were randomly separated into three groups (15 patients in eachgroup) receiving either 0.25 mg h-1 or 0.50 mg h-1 enalaprilat, respectively, orsaline solution as placebo (= control group). The infusion was continued for 5days.

3 Haemodynamic and respiratory parameters were intensively monitored on admis-sion to the intensive care unit (= 'baseline' values) and daily during the next 5days.

4 Mean arterial blood pressure (MAP) decreased significantly only in the enalaprilat-treated patients, whereas heart rate (HR) remained unchanged in these patients.

5 Pulmonary capillary wedge pressure (PCWP) and pulmonary artery pressure (PAP)were decreased by enalaprilat (0.50 mg h-1: PAP (mean ± s.d.) decreased from28.0 ± 4.1 to 24.0 ± 3.0 mm Hg) and remained significantly lower than in the con-trol group. In the untreated control group, cardiac index (CI), oxygen consumption(VO2I) and oxygen delivery (DO2I) significantly decreased, which was blunted byenalaprilat infusion. Oxygen extraction (02-extr) increased in both enalaprilatgroups (0.25 mg h-1: from 26.1 ± 5.5 to 30.4 ± 4.0%; 0.50 mg h-l: 25.2 ± 5.6 to30.9 ± 4.4%) and decreased in the control patients.

6 Right ventricular haemodynamics improved by enalaprilat infusion (0.50 mg h-1:RVEF increased from 40.0 ± 3.5 to 45.5 ± 4.0%). Lactate plasma concentrationsdecreased in the group with 0.50 mg h-1 enalaprilat (from 1.9 ± 1.0 to 1.3 ± 0.3mg dF-') and increased in the control patients.

7 Continuous infusion of the ACE inhibitor enalaprilat exerted beneficial cardio-respiratory effects in the critically ill. The widespread common risk of altered per-fusion with decreased CI, DO2, VO2, 02-extr and increased lactate concentrationwas blunted by enalaprilat infusion.

8 Although 0.5 mg h-1 enalaprilat was most effective, a dose of 0.25 mg h-1 alsoshowed beneficial haemodynamic effects in the critically ill.

Keywords angiotensin-converting enzyme inhibitors enalaprilat haemodynamicscritically ill circulation microcirculation organ perfusion right ventricular function

Introduction

The renin-angiotensin-system (RAS) plays a pivotal term blood pressure control by influencing sodium re-role in the regulation of cardiovascular homeostasis absorption and by directly and indirectly influencing[1]. The RAS is involved in short- as well as long- blood vessels. It is activated during 'stress response'

Correspondence: Professor Dr Joachim Boldt, Department of Anaesthesiology and Intensive Care Medicine, Klinikstrasse 29,Justus-Liebig-University Giessen, D-35392 Giessen, Germany

C) 1995 Blackwell Science Ltd 415

416 J. Boldt et al.

associated with major surgery [2], and it mediatessystemic hypertension. The RAS is also markedly in-volved in microcirculatory perfusion deficits: it hasbeen shown, e.g., that the RAS plays an importantrole in mediating the disproportionate splanchnichypoperfusion secondary to cardiogenic shock [3].

Angiotensin-converting enzyme (ACE) inhibitorsare established drugs for the treatment of patientswith hypertension and (chronic) heart failure [4]. Inmost reports, these substances were used orally. Withenalaprilat an ACE inhibitor is available which canbe used intravenously. Enalaprilat is the active diacidof the ACE inhibitor enalapril maleate [5].

The exact mechanisms of the vasodilating proper-ties of ACE inhibitors are not fully elucidated [6].The antihypertensive properties of these substancesappear to be most likely derived from their ability toprevent conversion of angiotensin-I to angiotensin-II[7]. In addition to systemic circulating RAS, local(endothelial-related) RAS may also play an importantrole in regulating haemodynamic homeostasis [8].Additional effects of ACE inhibitors such as interfer-ence with the degradation of bradykinin, accumula-tion of prostaglandin, and alteration of the release ofnoradrenaline influence their haemodynamic responseand contribute to vasodilation [9, 10].The beneficial haemodynamic effects of (oral) ACE

inhibitors in patients with chronic congestive heartfailure are well established [1, 4]. ACE inhibitors havealso been shown to protect against ischaemia/reperfu-sion injury. The benefit of (acute) interruption ofRAS during perioperative stress by single bolusadministration of ACE inhibitors has recently beendemonstrated [11]. Bolus injection, however, may beassociated with marked reduction in blood pressure-thus continuous i.v. administration of enalaprilatappears to be of advantage. Long-term, continuoususe of intravenous ACE inhibitors in the critically ill,however, has not been assessed. Thus it was the aimof the present study to investigate the cardiorespira-tory effects of continuous administration of the ACEinhibitor enalaprilat in two different dosages in criti-cally ill patients.

Methods

Patients and grouping

Forty-five consecutive patients from our surgicalintensive care unit (ICU) were prospectively studied.According to the protocol of the Ethics Study Com-mittee of the hospital, informed consent was obtainedfrom the closest relatives of all patients. The studyincluded patients with trauma (injury severity score(ISS) [12] >20) or patients requiring intensive caretherapy due to complications secondary to majorsurgery (no vascular or cardiac surgery patients). In-clusion criterion was a mean arterial blood pressure(MAP) of >75 mm Hg. Exclusion criteria were renalfailure (serum creatinine >2.5 mg dl-1; urine output<20 ml h-1), severe liver insufficiency, and haemo-

dynamic instability requiring catecholaminergic sup-port at baseline. Prospectively, the patients wererandomly separated into three groups:

group 1 (n = 15): 0.25 mg h-1 enalaprilat were con-tinuously administered,group 2 (n = 15): 0.50 mg h-1 enalaprilat wereinfused,group 3 (n = 15): saline solution was given asplacebo (= control group).

The infusion (of enalaprilat or placebo) was startedafter admission to the ICU (after baseline values weremeasured) and continued during the following 5 days.During the entire investigation period, lungs of allpatients were mechanically ventilated and a mixtureof fentanyl/midazolam was continuously infused. TheFIo2 was adjusted to keep Pao2 between 100 and150 mm Hg, Paco2 was maintained between 38 and45 mm Hg throughout the entire investigation period,and PEEP levels ranged from 5 to 12 cm H20 withoutshowing differences between the groups.To maintain filling pressures (central venous pres-

sure (CVP) and pulmonary capillary wedge pressure(PCWP)) >12 mm Hg but <18 mm Hg, low-molecularweight hydroxyethyl starch solution (6% HES, molwt: 200 000 Dalton, degree of substitution 0.5; Frese-nius, Bad Homburg, Germany) and Ringer's solutionwere infused. Packed red blood cells (PRBC) weregiven when haemoglobin was less than 9 g dl-F.

'Low-dose' dopamine was given in all patients(3 jg kg-' min-'). When cardiac index (CI) was <2.51 minm_ m2 in spite of sufficient volume therapy,adrenaline was administered. Noradrenaline was givenwhen MAP was <60 mm Hg and systemic vascularresistance (SVR) was <700 dyn s cm-5. Antibioticswere adapted according to daily microbiologicalscreening. The entire management of the patients(ventilation patterns, feeding, volume therapy) wascarried out by physicians who were not involved inthe study and blinded to the grouping. None of thepatients were operated upon during the study period.

Measured parameters and data points

Heart rate (HR), mean arterial blood pressure (MAP),pulmonary artery pressure (PAP), pulmonary capil-lary wedge pressure (PCWP), central venous pressure(CVP) and cardiac output (CO, thermodilution tech-nique) were monitored daily at 12.00 during a periodof haemodynanmic steady state of at least 30 min.Derived haemodynamic parameters were also calcu-lated (systemic vascular resistance (SVR), cardiac index(CI)). Right ventricular ejection fraction (RVEF),right ventricular end systolic and end diastolicvolumes (RVESV, RVEDV) were measured by ther-modilution technique (TD). The catheter is equippedwith a fast response thermistor (FRT; 50-100 ms) andtwo electrodes for intracardiac ECC recording. Thetypical downslope thermodilution washout curve fol-lows an exponential decay, interrupted by the dias-tolic plateaus. The ratio between the temperaturechange of two successive diastolic plateaus representsthe fraction of blood remaining in the right ventricle

© 1995 Blackwell Science Ltd, British Journal of Clinical Pharmacology, 40, 415-422

Cardiorespiratory effects of enalaprilat 417

(= residual fraction (RF)). Right ventricular ejectionfraction is calculated from EF = 1 - RF. The thermis-tor of the catheter is able to measure beat-to-beattemperature variations of the downstream temperaturechanges after injection of 10 ml ice-cold dextrose.The micropressor connected with the catheter deter-mines the best fit to the exponential curve, using aspecial algorithm. As cardiac output and strokevolume (SV) are also calculated by the microproces-sor ((Explorer, Baxter, Irvine, CA), RVEDV can bederived from SV/RVEF and RVESV = RVEDV - SV.

Blood gas analyses were carried out from arterialand mixed-venous blood samples. Oxygen consump-tion index (VO2I), oxygen delivery index (DO2I), andoxygen extraction (02-extr) were calculated fromstandard formulae using the same monitoring system(Explorer, Baxter, Irvine, CA). Plasma lactate con-centrations were measured from arterial bloodsamples. All measurements were carried out on theday of admission (= 'baseline' values) and daily forthe next 5 days at 12.00 h.

All patients were scored by physicians who werenot involved in the study and blinded to the groupingof the patients. 'Sepsis' was defined using the guide-lines of the members of ACCP/SCCM [13], acute res-piratory distress syndrome (ARDS) was assessedaccording to Murray and colleagues [14].Mean ± standard deviation (s.d.) was calculated

for all data at every data point. One-way and two-

way analysis of variance (ANOVA) with repeatedmeasures were used to determine the effects ofgroup, time, and group-time interaction for eachmeasured parameter. P values <0.05 were consideredsignificant.

Results

Patients' demographics and intensive care treatment

Patients' characteristics and data from intensive caretherapy did not differ between the groups (Table 1).The underlying disease, scoring at baseline, and sur-vival rate during the study period were also withoutsignificant differences. The cumulative fluid balancewas higher in both enalaprilat groups than in thecontrol patients (P < 0.05) (Table 1). APACHE IIdecreases only in group 2 and showed the lowestvalue at the end of the study (Table 2). None of thepatients suffered from severe side-effects (criticaldrop of MAP (<55 mm Hg), acute renal failure(serum creatinine never exceeded 2.0 mg dl-1) orliver dysfunction during the study period.

Differences in haemodynamics between enalaprilat-and placebo-treated groups were mostly significantfrom the second day on. Thus 95% confidence inter-val for mean differences were calculated for thesecond day of treatment (Table 3).

Table 1 Patients' characteristics and data from intensive care management(mean ± s.d.)

Enalaprilat0.25 mg h-1 0.5 mg h-

Age (years)range

Weight (kg)range

Gender (M/F)

50± 1334 to 6582± 11.965 to 958/7

52 ± 1424 to 6580.1 ± 13.172 to 939/6

Patients' underlying disease on admission to ICUP.o. complications 9 8Trauma 6 7ARDS 2 1Survivors 13 13Non-survivors 2 2

Patients' scoring on admissionAPACHE II score 18 ± 2ISS 25 ± 3

19 ± 324± 3

Controlgroup

49± 1425 to 6477.3 ± 10.167 to 906/9

962

123

19 ± 325 ± 3

Catecholaminergic supportAdrenaline (number)

(range (ig min-,))Noradrenaline (number)

(range (gg min-,))Dopamine (number)

(range (,ug min-,))Cumulative fluid balanceAt 5th day (ml)

45

all all200 to 270 200 to 300

+2050 ± 380 +2450 ± 250

ICU: intensive care unit; ISS: injury severity score; ARDS: acute respiratory distresssyndrome; p.o.: postoperative.*P < 0.05 different from the enalaprilat groups.

1995 Blackwell Science Ltd, British Journal of Clinical Pharmacology, 40, 415-422

35 to 825 to 8all200 to 290

+850 ± 180*

418 J. Boldt et al.

Table 2 Number of patients at each data point, changes in APACHE II score and plasma lactate levels during the study period(mean ± s.d.)

Parameter Group Baseline Ist day 2nd day 3rd day 4th day 5th day

Number of 0.25 mg h-1 E 15 15 15 15 15 13patients 0.50 mg h-1 E 15 15 15 15 14 13

Control 15 15 15 14 12 12

APACHEII 0.25mgh- E 18±2 17±3 17±2 17±3 16±3 15±3score 0.50mgh- E 19±3 16±3 15±2 14±3 13±3* 13±3*

Control 19±3 19±3 21±2 21±3 20±3 21±3

Lactate 0.25 mg h-1 E 1.7 ± 0.9 1.5 ± 0.8 1.6 ± 0.6 1.6 ± 0.4 1.4 ± 0.5 1.5 ± 0.3(mg dl-1) 0.50 mg h-' E 1.9 ± 1.0 1.5 ± 0.6 1.3 ± 0.5 1.3 ± 0.3 1.2 ± 0.3 1.2 ± 0.6

Control 1.7 ± 0.9 1.9 ± 0.8 2.7 ± 0.5* 2.9 ± 1.4* 2.4 ± 0.5* 2.3 ± 0.5*

E: enalaprilat.*P < 0.05 different from the other groups.

Table 3 95% confidence interval for mean differences ± s.d.(baseline-2nd day of treatment) in the three groups

Difference: 95% confidencebaseline - 2nd day interval

MAP (mm Hg)0.25 mg h-' E0.5 mg h-1 EControl

HR (beats min-1)0.25 mg h-1 E0.5 mg h- EControl

PAP (mm Hg)0.25 mg h- E0.5 mg h- EControl

PCWP (mm Hg)0.25 mg h-1 E0.5 mg h-1 EControl

CI (1 min-n2)0.25 mg h-' E0.5 mg h-' EControl

RVEF (%)0.25 mg h-' E0.5 mg h-' EControl

Pao2/FIo2 (mm Hg)0.25 mg h- E0.50 mg h-' EControl

VO2I (ml min-nm2)0.25 mg h-' E0.5 mg h-i EControl

DO2I (ml min-I m2)0.25 mg h-' E0.5 mg h-1 EControl

5.1 ± 8.28.5 ± 6.6

-1.7 10.8

6.6 9.37.5 11.6

-11.6±10.9

4.3 3.05.1 3.3

-2.1 ±4.5

3.1 ± 3.05.6 ± 2.60.5 ± 3.7

-0.54 ± 0.81-0.63 ± 0.700.35 ± 0.79

-2.1 ± 5.1-6.4 ± 5.07.8 ± 3.5

-20.1 ± 59.4-31.1 ± 37.076.0 ± 44.2

-13.5 ± 38.5-12.1 ± 32.024.8 ± 19.1

-2.3 + 93.2-37.5 ± 121.478.9± 117.3

0.9; 9.15.1; 11.74.3; -7.7

1.9; 11.52.3; 13.3

-6.5; -16.7

2.7; 5.93.4; 6.9

-0.4; -4.4

1.5; 4.64.3; 6.9

-1.4; 2.2

-0.98; -0.24-0.34; 0.23-0.13; 0.18

-5.1; 1.0-3.7; -8.96.0; 9.5

6.2; -32.0-12.2; -51.153.2; 98.6

-33.2; 6.44.5; 41.8

14.5; 33.8

-49.3; 45.429.1; 103.817.5; 143.3

Systemic and pulmonary haemodynamic data

MAP dropped significantly in the patients who hadreceived enalaprilat (0.25 mg h-1: from 87.4 ± 6.2 to82.4 ± 6.1 mm Hg; 0.50 mg h-1: from 87.1.9 ± 5.2 to77.0 ± 7.1 mm Hg), without, however, showing signi-ficant differences between these two groups (Figure1). MAP remained lower in both enlaprilat groupsthan in the untreated control patients until the end ofthe investigation period (P < 0.05). HR was un-changed by enalaprilat infusion (Table 3), but in-creased in the non-treated patients (from 101 ± 11 to99 ± 11 to 113 ± 9 beats min-' at day 2 (P < 0.05). Inboth enalaprilat groups, PAP decreased significantly(0.25 mg h-1: from 27.0 ± 3.5 to 23.1 ± 2.5 mm Hg;0.50 mg h-1: from 28.0 ± 4.1 to 22.1 ± 3.0 mm Hg),whereas it increased in the control patients (Figure1). PCWP was comparable at baseline in all groups.It decreased similarly in both enalaprilat groups (P <0.05) and was significantly lower than in the controlpatients throughout the study period (Figure 1). Atbaseline, CI did not differ between the three groups.In the further course of the study, it decreased in thecontrol group (from 3.30 ± 0.9 to 2.81 ± 0.7 1 min-1m2) and slightly increased in both enalaprilat groupsbeing significantly different to the CI in the controlgroup (Figure 1). SVR decreased by the enalaprilatinfusion (no difference between these groups) andsignificantly increased in the control patients.

Right ventricular haemodynamics

RVEF remained almost unchanged in the patients withlow-dose enalaprilat and increased in patients who havereceived high-dose enalaprilat (from 40.0 ± 3.5 to45.9 ± 4.0%; P < 0.05) (Figure 2). RVEF significantlydecreased in the control patients (from 39.3 ± 3.8 to29.5 ± 5.9%) and was different from the RVEF inboth enalaprilat groups (P < 0.05) (Figure 2). Rightventricular loading (RVEDV, RVESV) increased in



34

32

IE

0-

0-

30

28

26

24

22

0 1 2 3 4 5

5.0

4.5

4.0

E 3.5_-

3.0

2.5I I20 1 2 3 4 5

I

0 1 2 3 4 5

*

0 1 2 3 4 5

Figure 1 Changes (mean ± s.d.) in mean arterial pressure (MAP), pulmonary artery pressure (PAP), pulmonary capillarywedge pressure (PCWP), and cardiac index (CI). * 0.25 mg h'1 enalaprilat, 0 0.5 mg h-1 enalaprilat, A control. Datapoints: 0: 'baseline' value; 1: 1st day; 2: 2nd day; 3: 3rd day; 4: 4th day; 5: 5th day. *P < 0.05 different from theenalaprilat groups.

Ewcc

0 1 2 3 4 5

coIE

0-

280

260

240

220

200

180

160

140

20

18

16

14

12

, i I

0 1 2 3 4 5

*

I I I.0 1 2 3 4 5

I I -1 J

0 1 2 3 4 5

Figure 2 Changes (mean ± s.d.) in right ventricular ejection fraction (RVEF), right ventricular end diastolic volume(RVEDV), right ventricular end systolic volume (RVESV), and central venous pressure (CVP). * 0.25 mg h-1 enalaprilat,0 0.5 mg h-' enalaprilat, A control. Data points see Figure 1. *P < 0.05 different from the enalaprilat groups.

1995 Blackwell Science Ltd, British Journal of Clinical Pharmacology, 40, 415-422

100

0IE

0-CL

95

90

85

80

22

20

18

16

IEE

0-

0-

14

12

50

45

~-R

CRLLwU 40 _

35 F

30

200

180

160

140

E

cnCR)w

120

100

80

420 J. Boldt et al.

the control patients (P < 0.01) and remained un-changed in both enalaprilat groups (Figure 2). CVPshowed similar data in all three groups within theentire study period (Figure 2).

Oxygenation and laboratory parameters

Pao2/FIo2 ratio remained stable in both enalaprilatgroups, but it decreased significantly in the controlpatients (Figure 3). Both D021 and V021 increasedin the enalaprilat groups, and were significantly lowerin the control patients (Figure 3). 02-extraction in-creased in the patients who had received enalaprilatcontinuously (0.25 mg h-1: from 26.1 + 5.5 to 30.4 ±4.0%; 0.50 mg h-1: 25.2 + 5.6 to 30.9 ± 4.4%) and itdecreased in the non-treated control group (Figure 3).Lactate plasma levels decreased most pronouncedlyin those patients in whom 0.50 mg h-1 enalaprilat wasgiven (from 1.9 ± 1.0 to 1.2 ± 0.3 mg dl-') (P < 0.05)and increased in the control patients (Table 2).

Discussion

The continuous i.v. administration of the ACE in-hibitor enalaprilat in our intensive care patientsshowed overall beneficial cardiorespiratory effects.Enalaprilat resulted in vasodilation in arterial vesselsand (to a lesser degree) also in the capacitance

IEE

a-0-

340

320

300

280

260

240

220

200

200

180

160

140

120

4-0xw

6'

I I~~

0 1 2 3 4 5

system: MAP was significantly reduced and remainedlower than baseline values throughout the studyperiod, fluid balance was higher in both enalaprilatgroups indicating increased venous pooling. As alsoshown by others using single bolus injection [15, 16],continuous i.v. enalaprilat was not associated with anincrease in HR via reflex tachycardia.

Right ventricular haemodynamics were also bene-ficially influenced by continuous infusion of enalapri-lat. Right ventricular function is known to be oftenimpaired in the critically ill [17], which was con-firmed by the changes of RVEF in our untreated con-trol patients. Enalaprilat resulted in an improvementin right ventricular haemodynamics (increase inRVEF and a decrease in filling volumes (RVEDV,RVESV)), which was sustained throughout the entirestudy period. In patients with significantly impairedleft ventricular function, 1.25 mg enalaprilat reducedventricular filling volumes (RVEDV, RVESV) andincreased RVEF significantly. These effects appear tobe most likely due to beneficial actions of enalaprilaton left ventricular loading, which positively in-fluences right ventricular function via ventricularinterdependence [19]. In the present study, PAP wasalso reduced by enalaprilat, which may have contri-buted to the improved right ventricular function viareduction of right ventricular afterload.

Doses of enalaprilat given intravenously vary widelyin the different studies ranging from 0.625 mg [20]to 40 mg [21]. In chronic congestive heart failure

750 -

700 -

'c 650

600-

6' 550-a

36

34

32

30

28

26

24

22

20

*

I ..I I I

0 1 2 3 4 5

Figure 3 Changes (mean ± s.d.) in Pao2/FIo2 ratio, oxygen delivery index (DO21), oxygen consumption index (VO2I),and oxygen extraction (O2-extr). * 0.25 mg h-1 enalaprilat, 0 0.5 mg h-1 enalaprilat, A control. Data points see Figure 1.*P < 0.05 different from the enalaprilat groups.


I l


(CHF), 0.625 mg enalaprilat appears to be enough toproduce significant inhibition of angiotensin-convert-ing enzyme and induce maximum haemodynamicresponse [16]. LeJemtel and colleagues [22] reportedon the similarity of the peak haemodynamic responseto 1.25 and 5.0 mg i.v. administered enalaprilat inpatients suffering from CHF (NYHA III and IV).Systemic arterial blood pressure decreased by 16%and 14%, respectively, whereas CI increased by 16%and 25%. Also Kubo and colleagues [23] showed nofurther reduction in blood pressure and PCWP whenthe dose of enalaprilat was increased. In the presentstudy, total daily dose added up to approximately 6 mg(group 1) and 12 mg (group 2) enalaprilat, respec-tively. MAP and PAP were slightly more reduced,RVEF and 02-extraction were more pronouncedlyincreased by 0.5 mg h-1 than by 0.25 mg h-1 enalapri-lat. Plasma lactate level was more beneficiallyinfluenced when the higher dose of enalaprilat wasgiven. However, most of the cardiorespiratory para-meters of our patients already differed significantlybetween the low-dose enalaprilat group and the non-treated control patients. Thus in patients with lowerMAP, 0.25 mg h-1 enalaprilat can be used and mostof the beneficial haemodynamic effects can beensured nonetheless.

Blood pressure reducing properties of i.v. admin-istration of enalaprilat [24, 25] were confirmed bythe present data. Blood pressure remained lower thanbaseline values throughout the entire study period inboth enalaprilat groups indicating no tachyphylaxiswith continuous use of the substance. Owing to thesometimes marked decrease in blood pressure sec-ondary to ACE inhibitor injection [26], it has beensuggested that it should be administered by controlledinfusion rather than by (intermittent) bolus injection.

There is good evidence that severe disturbances ofmicrocirculation are involved in the development ofmultiple-organ failure (MOF) in the critically ill [27].It seems that the vasoregulatory systems which areneeded to control the distribution of cardiac outputmay be impaired in this situation [28]. Additionally,microcirculatory dysfunction is common in thesepatients. Vasopressin and angiotensin-II are known tomediate peripheral perfusion deficits [29]. Both sub-stances cause splanchnic vasoconstriction althoughthere is a marked increase in need for oxygen de-livery in this situation [30]. The increase in gutmucosal permeability with the risk of bacterial trans-location appears to be most likely secondary to adecrease in splanchnic blood flow. The influence ofACE inhibitors on organ perfusion has not yet beencompletely elucidated. ACE inhibitors have beenshown to maintain or even improve blood flow tovital organs [31]. In an animal experiment, enalaprilat(1 mg kg-' i.v.) exerted protective effects against post-

ischaemic renal failure [32]. These positive effectsmay most likely result from the beneficial macro- andmicrocirculatory actions of the ACE inhibitors or bythe inhibition of (local) angiotensin-II production.Additionally, some of these substances are reported toact as free oxygen radical scavengers [33].

Disturbance in the vascular control might play animportant role in the genesis of extraction defects intissues in the critically ill. Alterations in micro-regional perfusion may result in some capillaryregions to be overperfused while others will beunderperfused relative to 02 needs [34]. Detrimentalredistribution of local blood flow due to inappropriatevasoconstriction appears to be one of the most impor-tant sequels in the critically ill. In the present study,CI, V02 and DO2 were maintained at higher levels byinfusion of enalaprilat than in the untreated controlgroup. Shoemaker and colleagues [35] demonstratedthe importance of maintaining V02 and DO2 atelevated levels to reduce the incidence of multiple-organ failure and overall mortality. Whether an in-creased V02 associated with an increased DO2represents a lesser extent of tissue hypoxia cannot beanswered for certain at present. 02-extraction wasincreased by infusion of enalaprilat thus indicating animproved perfusion at the microcirculatory level.The use of ACE inhibitors such as enalaprilat was

reported to be associated with the risk of severe side-effects. Deleterious effects on renal function havebeen described [36]. In the present study, however,renal dysfunction could not be observed. Accordingto Licker & colleagues [37], patients on chronic (oral)ACE inhibitors may need higher doses of alpha-receptor agonists than patients with an unimpairedRAS. Also this effect could not be confirmed by thepresent data: in both low-dose and high-dose regimeenalaprilat there was no need for noradrenaline infu-sion to counteract the vasodilating properties of thesubstance.

It can be summarized that the renin-angiotensinsystem appears to play an important role in the patho-physiology of macro- and microcirculatory abnormal-ities in the critically ill. Critical illness normallyresults (more or less) in circulatory derangementswith the risk of critical perfusion deficits. Continuousi.v. administration of the ACE inhibitor enalaprilatexerted sustained beneficial haemodynamic effects inour patients. Continuous infusion of 0.50 mg h-1enalaprilat resulted in overall more improvements ofcardiorespiratory parameters associated with a morepronounced decrease in blood pressure, but the lowerdose (0.25 mg h-1) also showed beneficial haemo-dynamic effects. Our results encourage further in-vestigations to assess the exact role of ACE inhibitorsin this situation.

References

1 Colson P. Angiotensin-converting enzyme inhibitors incardiovascular anesthesia. J Cardiothorac Vasc Anesth1993; 7: 734-742.

2 Colson P, Ribstein J, Mimran M, Grolleau D, ChaptalPA, Roquefeuil B. Effect of angiotensin convertingenzyme inhibition on blood pressure and renal function

i 1995 Blackwell Science Ltd, British Journal of Clinical Pharmacology, 40, 415-422

422 J. Boldt et al.

during open heart surgery. Anesthesiology 1990; 72:23-27.

3 Bailey RW, Bulkley GB, Hamilton SR, Morris JB,Haglund UH. Protection of the small intestine fromnonocclusive mesenteric ischemic injury due to cardio-genic shock. Am J Surg 1987; 153: 108-116.

4 Edwards CR, Padfield PL. Angiotensin-converting en-zyme inhibitors. Past, present, and bright future. Lancet1985; i: 30-34.

5 Abraham WB, Davies RO, Gomez HJ. Clinical pharma-cology of enalapril. J Hypertens 1984; 2 (suppl 222):231.

6 Ujhelyi MR, Ferguson RK, Vlasses PH. Angiotensin-converting enzyme inhibitors: mechanistic controversies.Pharmacotherapy 1989; 9: 351-362.

7 Antonaccio MJ, Wright JJ. Renin-angiotensin system,converting enzyme, and renin inhibitors. In Cardio-vascular pharmacology, ed Antonaccio MJ. RavenPress, New York, 1990; 201-228.

8 Unger T, Gohlke P. Tissue renin-angiotensin systems inthe heart and vasculature: possible involvement in thecardiovascular actions of converting enzyme inhibitors.Am J Cardiol 1990; 65: 31-1OT.

9 Johnston CI, Jackson B, Cubela R, Arnolda L. Mecha-nism for hypotensive action of angiotensin convertingenzyme inhibitors. Clin Exp Hypertens 1984; 6: 551-561.

10 Dickstein K, Till AE, Aarsland T, et al. The pharmaco-kinetics of enalaprilat in hospitalized patients with con-gestive heart failure. Br J Clin Pharmacol 1987; 23:403-410.

11 Mirenda JV, Edwards CS, Crawford JJ, Wolff PR. Useof intravenous enalaprilat for hypertension followingmyocardial revascularization. Ilth Meeting of Cardio-vascular Anesthesiologists, Boston, 1992, Abstractbook: 263.

12 Baker SP, O'Neill B. The injury severity score: an up-date. J Trauma 1976; 16: 882-888.

13 Members of the American College of Chest Physicians/Society of Critical Care Medicine Conference Com-mittee: American College of Chest Physicians/Societyof Critical Care Medicine Consensus Conference. De-finitions for sepsis and organ failure and guidelines forthe use of innovative therapies in sepsis. Crit Care Med1992; 20: 864-874.

14 Murray JF, Murray MA, Luce JM, Flick MR. An ex-panded definition of the adult respiratory distress syn-drome. Am Rev Resp Dis 1988; 138: 720-723.

15 Reid JL, Milar JA, Campbell BC. Enalaprilat and auto-nomic reflexes and exercise performance. J Hypertens1983; 1:129-134.

16 Chatterjee K, Opie L. Angiotensin inhibitors and othervasodilators with special reference to congestive heartfailure. Cardiovasc Drugs Ther 1987; 1: 1-8.

17 Hoffman MJ, Greenfield LL, Sugerman HJ, Tatum JL.Unsuspected right ventricular dysfunction in shock andsepsis. Nucl Med 1983; 198: 307-312.

18 Sibbald WS, Drieger AA. Right ventricular functionin acute disease states: Pathophysiologic consideration.Crit Care Med 1983; 11: 339-345.

19 Konstam MA, Kronenberg MW, Udelson JE, et al.Effects of acute angiotensin converting enzyme in-hibitor on left ventricular filling in patients with con-gestive heart failure. Circulation 1990; 81 (suppl III):TII 115-III122.

20 Acampora GA, Melendez JA, Keefe DL, Turnball AD,Bedford RF. Intraoperative administration of the intra-venous angiotensin-converting enzyme inhibitor, enala-prilat, in a patient with congestive heart failure. AnesthAnalg 1989; 69: 833-839.

21 DiPette DJ, Ferraro JC, Evans RR, et al. Enalaprilat, anintravenous angiotensin-converting enzyme inhibitor, inhypertensive crisis. Clin Pharmacol Ther 1985; 38:199-204.

22 LeJemtel TH, Chatterjee K, Walinsky P, et al. Acuteand sustained angiotensin-converting enzyme inhibitionin chronic heart failure: double-blind evaluation of twodosage regimes. Heart Failure 1988; 4: 182-187.

23 Kubo S, Cody Laragh JH. Immediate converting en-zyme inhibition with intravenous enalaprilat in chroniccongestive heart failure. Am J Cardiol 1985; 55:122-126.

24 Strauss R, Gavras I, Vlahakos D, Gavras H. Enalaprilatin hypertensive emergencies. J Clin Pharmacol 1986;26: 39-43.

25 Rutledge J, Ayers C, Davidson R, DiPette D, GuthrieG, Fisher M, Schwartz S, Rucinska E. Effect of intra-venous enalaprilat in moderate and severe systemichypertension. Am J Cardiol 1988; 62: 1062-1067.

26 Reid JL, MacFadyen RJ, Squire IB, Lees KR. Angio-tensin-converting enzyme inhibitors in heart failure:blood pressure changes after the first dose. Am Heart J1993; 126: 794-799.

27 Kirkpatrick CJ, Klosterhalfen B, Hauptmann S. Therole of the endothelium in multiple organ failure. InYearbook of intensive care and emergency medicine, edVincent JL. Springer, Berlin; Heidelberg New York,1992; 14-24.

28 Wylam ME, Samsel RW, Mitchell RW, Leff AR,Umans JG, Schumacker PT. Endotoxin in vivo impairsendothelium-dependent relaxation of canin arteries invitro. Am Rev Resp Dis 1990; 142: 1263-1267.

29 Kostis JB, DeFelice EA, Pianko LJ. The renin-angiotensin system. In Angiotensin converting enzymeinhibitors, eds Kostis JB, DeFelice EA. Alan R Liss,New York, 1987; 1-18.

30 McNeill JR, Stark RD, Greeway CV. Intestinal vaso-constriction after haemorrhage: roles of vasopressin andangiotensin. Am J Physiol 1970; 219: 1342-1347.

31 Creager MA, Halperin JL, Bernard DB, et al. Acuteregional circulation and renal hemodynamic effects ofconverting enzyme inhibition in patients with conges-tive heart failure. Circulation 1981; 64: 483-489.

32 Long GW, Misra DC, Juleff R, Blossom G, Czako PF,Glover JL. Protective effects of enalaprilat againstpostischemic renal failure. J Surg Res 1993; 54:254-257.

33 Przyklenk K, Kloner RA. Relationship between struc-ture and effects of ACE inhibitors: comparative effectsin myocardial ischemic/reperfusion injury. Br J ClinPharmacol 1989; 28: 167S-175S.

34 Cain SM. Tissue hypoxia in animal models of sepsis. InYearbook of intensive care and emergency medicine, edVincent JL. Springer, Berlin, Heidelberg New York,1992; 281-293.

35 Shoemaker WC, Appel P, Kram H. Clinical trial of analgorithm for outcome prediction in acute circulatoryfailure. Crit Care Med 1982; 10: 390-393.

36 Linas S. Calcium channel blocker versus angiotensin-converting enzyme inhibitors: renal effects. Am J Kid-ney Dis 1990; 4 (suppl 1): 15-19.

37 Licker M, Neidhart, P, Lustenberger S, Kalonji T. Vas-cular alpha1-adrenergic responsiveness during cardiacsurgery in patients on chronic angiotensin-convertingenzyme inhibitors. European Society of CardiothoracicAnaesthesiologists 1992; Abstract book: 65.

(Received 8 February 1995,accepted 3 July 1995)


Documents

Cardiorespiratory effects of continuous i.v. administration of the ACE