Norepinephrine or Dopamine for the Treatment of Hyperdynamic Septic Shock?

clinical investigations in critical care Norepinephrine or Dopamine for the Treatment of Hyperdynamic septic Shock?* Claude Martin, M.D., F.C.C.R; Laurent Papazian, M.D.; Gilles Perrin, M.D.; Pierre Saux, M.D.; and Francois Gouin, M.D.

Study objective: To compare the ability of dopamine and norepinephrine to reverse hemodynamic and metabolic abnormalities of human hyperdynamic septic shock. Design: Prospective, double-blind, randomized trial. Setting: An leu in a university hospital. Ibtients: Adult patients with hyperdynamic septic shock after Ruid resuscitation. Interventions: Patients were assigned to receive either dopamine (2.5 to 25 fl.g/kglmin) or norepinephrine (0.5 to 5.0 Jl.glkg/min). If hemodynamic and metabolic abnormalities were not corrected with the maximum dose of one drug, the other was added. Measurements and results: The aim of therapy was to achieve and maintain for at least 6 h all of the following: (1) systemic vascular resistance index> 1,100 dynes-s/em'-m" and/or mean systemic blood pressure ~80 mm Hg, (2) cardiac index ~4.0 Umin/m2 ; (3) oxygen delivery >550 mil min/m-, and (4) oxygen uptake> 150 ml/min/m", With the use of dopamine 10 to 25 Jl.g/kglmin, 5 of 16 patients (31 percent) were successfully treated, as compared with 15 of 16 patients (93 percent) by norepinephrine at a dose of

1.5 ± 1.2 Jl.g/kg/min (p
shock that persists after blood volume expanSeptic sion is often hemodynamically characterized by

inappropriate use of potent vasopressor agents leads to tissue hypoperfusion and severe ischemia of vital organs." Newer catecholamines were made available for the treatment of shock states and among them, dopamine is widely recommended for the treatment of septic shock because it increases systemic blood pressure by a combined action on myocardial performance and systemic vascular resistance .14-16 However, in many patients, dopamine fails to restore adequate hemodynamic conditions, and norepinephrine has been found to be beneficial.P''? So far, to our knowledge, there has been no conclusive study comparing the two drugs. This prospective, randomized, doubleblind study was performed to compare the ability of norepinephrine and dopamine to reverse hemodynamic abnormalities of human hyperdynamic septic shock. Since hemodynamic management of septic shock is also aimed at improving the oxygen supply to organs, the effects ofboth drugs on oxygen metabolism were also studied.

hypotension, systemic vasodilation, and high cardiac index (CI).1-3 Metabolically, hyperdynamic septic shock is characterized by a reduced oxygen uptake and an abnormal flow dependence of index of O 2 uptake (IVo 2) 011 index of O 2 delivery (IDo2) even at a normal or high delivery rate.r'' According to hemodynamic monitoring, and after fluid challenge, inotropic agents with vasoconstrictive properties are commonly used to reverse hyperdynamic septic shock. Early studies showed that norepinephrine could be effective, but because of the lack of routine hemodynamic monitoring and the fears of excessive vasoconstriction, this drug is not widely used. 10-12 Indeed, the

*Fro II 1

the Department of Intensive Care, Sainte Marguerite Hospital, and the Department of Intensive Care, Nord Hospital, Marseilles, University School of Medicine, Marseilles, France. Manuscript received September 16; revision accepted November 25. Reprint requests: Dr. Martin, Hopital Ste Marguerite, Reanimation, 13326 Marseille Cedex 15, France

1826

= = =

= = =

=

CaOI arterial oxygen content; CI cardiac index; CvO l mixed venous oxygen content; CVP = central venous pressure; IDol index of oxygen delivery; IVo l index of oxygen uptake; MBP mean blood pressure; MPAP mean pulmonary artery pressure; O. ext = oxygen extraction rate; PCWP = pulmonary capillary wedge pressure; SBP = systolic blood pressure; SVRI = systemic vascular resistance index

Norepinephrine or Dopamine in Septic Shock? (Martin at a/)

METHODS

This prospective, randomized, double-blind study included 32 consecutive patients presenting with hyperdynamic septic shock. The study received approval of the Ethics Committee of our Institution, and written informed consent was obtained from a close relative. Hyperdynamic septic shock was defined as follows: (1) systolic blood pressure (SBP) of less than90 mm Hg; (2) CI of more than 4.0 Uminlm 2 ; (3) decreased organ perfusion as evidenced by altered mental status (prior to sedation) and/or oliguria (less than 30 ml/h), (4) arterial blood lactate levels greater than 2.5 mmoVL; and (5) bacteremia, or in patients undergoing concomitant broadspectrum antibiotic treatment, an identified source of infection. All patients had a body temperature greater than 38.SOC.

Hemodynamic and Metabolic Studies Heart rate was monitored continuously. Arterial pressure was monitored via an arterial catheter (radial artery). All patients had their pulmonary artery catheterized with a Swan-Ganz catheter. Serial measurements of heart rate (H8), mean blood pressure (MBP), central venous pressure (CVP), mean pulmonary artery pressure (MPAP) and pulmonary capillary wedge pressure (PCWP) were made. All pressures were measured at end-expiration with the patient in the supine position. Transducers were referenced to the midaxillary line. In all patients, cardiac output was recorded in triplicate by the thermodilution technique, using ice chilled «2°C) 10 ml 5 percent dextrose injections performed at end-expiration. Oxyhemoglobin saturation and oxygen content were measured in systemic and pulmonary arterial blood using an oximeter (IL 282, Instrumentation Laboratories, Lexington, Mass). Derived hemodynamic variables were calculated as follows: systemic vascular resistance index (SVRI) (dynes-s/cms-ms) = ([MBP - CVP]lCI) x 80; VOl (ml/min/m'') = (a - V)OI x CI x 10 where (a - v)O. = arteriovenous oxygen difference; Dol (mVminlml ) = arterial O 2 content (CaOJ x CI x 10; O. extraction rate (Oll ext) (%)= CaO I - mixed venous O. content (CvOJ/CaOI • Urine was collected via an indwelling bladder catheter. Lactate samples were drawn from the arterial catheter,

Therapeutic Protocol Patients received broad-spectrum antibiotic coverage. None of these patients received corticosteroids. Because of severe hypoxia due to acute pneumonia in 18 patients and adult respiratory distress syndrome in the remaining patients, respiratory support was needed in all patients. Adult respiratory distress syndrome was characterized by bilateral homogeneous pulmonary opacifications on chest radiographic examination, and marked arterial hypoxemia lower than 60 mm Hg at FIo!=O.50. TIdal volume, respiratory rate, and Flo! were adjusted to maintain normal pH and PaCO. value and to keep PaO. above 70 mm Hg. All patients received volume expansion that was started before the pulmonary artery catheter was in place. Indication of volume expansion was a CVP of less than 12 mm Hg. Fluid resuscitation consisted of colloid and crystalloid solutions, and blood hematocrit was maintained greater than 33 percent with blood transfusion. Once the pulmonary artery catheter was in place, left ventricular preload was estimated from PCWP and was considered optimal when, at a given level, additional Huid infusion was no longer accompanied by an increase in CI. Fluid resuscitation was also discontinued when PaO I showed a marked decrease (more than 15 percent), which was the case in seven patients. To be included in the stud); after optimal ventilatory management and fluid resuscitation, the patients had to present all of the following: (1) SBP of less than 90 mm Hg, (2) SVRI of less than 1,000 dynes-s/cms-ms, (3) CI greater than 4.0 Uminlm l ; (4) persistent oliguria (less than 30 mJlh); and (5) arterial blood lactate level greater than 2.5 mmoVL. When patients fuHilled these inclusion criteria, a continuous infu-

sion of either dopamine or norepinephrine was started via a separate central venous line and an automatic pump. Dopamine was used as an original solution containing 40 mg/ml and norepinephrine, 2 mgt ml, For each patient, two drug dilutions were prepared. One contained dopamine diluted so that an infusion rate of 2 mVmin allowed us to deliver 2.5 ...glkgtmin to the patient. Two-milliliter increments were allowed up to a maximum dose of 25 ....glkgtmin (infusion rate, 20 mVmin). The other solution contained norepinephrine diluted so that an infusion of 2 mVmin allowed us to deliver to the patient 0.5 ...glkgtmin. Two-milliliter increments were allowed up to a maximum dose of5 ....~glmin (infusion rate, 20 mV min). Then each patient received either dopamine or norepinephrine, according to the randomization code. Dopamine was started at a dose of 2.5 ....glkgtmin and norepinephrine was started at a dose of 0.5 ...,~glmin (ie,2 mVmin for each patient). Then catecholamine doses were increased by 2 mllmin or multiples of 2-mVmin increments after 5- to Io-minute intervals when hemodynamic abnormalities were not corrected. A maximal infusion rate of 20 mil min was used (dopamine, 25 ....glkgtmin; norepinephrine, 5 ...glkgt min). At no time was the physician in charge of the patient aware of the drug being infused. The aim of therapy was to achieve and maintain for at least 6 consecutive hours all of the following: (1) SVRI greater than 1,100 dynes-s/cms-m! and/or MBP greater than 80 mm Hg; (2) CI greater than 4.0 Umin/ml; (3) IDol greater than 550 mllmin/m·; and (4) IV0 1 greater than 150 ml/min/m". If the therapeutic goals were not fulfilled with the use of the maximal dose, the catecholamine dose infusion was continued, the other drug was added, and doses were progressively increased as described above. Once hemodynamic stabilization was obtained, drug titration was modified, when needed, according to the hemodynamic assessments performed every 2 h. Fluids were given to maintain PCWP at the previously determined optimal level. Catecholamines were continued until recovery or death. Statistics Data are reported as mean ± SD. Repeated measures analysis of variance and the Student-Newman-Keuls' test were used to evaluate differences between groups with respect to change over time. Within-group variabilities were tested using two-way analysis of variance and means were then compared by Duncan's multiple range test. A two-sided p value of <0.05 was considered statistically significant. RESULTS

Thirty-two patients were included in the study Table 1 shows that at the time of inclusion in the study, no difference was observed between the two groups with regard to clinical data of the 32 patients, Table 2 shows that at the time of inclusion to the study, no Table I-Clinical DattJ of the Two Gmu".

Age, yr Weight, kg Men Women APACHE II score Causes of septic shock Peritonitis Pneumonia Septicemia Miscellaneous

Dopamine (0= 16)

Norepinephrine (n= 16)

53±I9 65±I4 12

52±12 62±I7 12

4

4

30± 1.2

3I±1.3

5

2 10 1 3

8 1 2

CHEST I 103 I 6 I JUNE, 1993

1827

Table I-Hemodynamic and Metabolic DtJtIJ of the Patienta Who Reaponded to Norepinephrine or Dopamine + Norepinephrine· Dopamine

Norepinephrine

MB~mmHg

HR, beat/min CI, Umin/ml PC~mmHg

SVRI, dyn.sec/cms-m" MPA~mmHg

0. ext lDo., mVminlm· IVo., mVmin/m l Urine output, ml/h Lactate, mmoVL

Baselinet

NoJ1

Nor+6hi

Baseline§

25 p.gJl

Dop+Noril

Dop+ Nor+6 hli

54±10 113±21 5.3± 1.3 12±3 659±221 24±5 0.26±0.10 B01±231 208±70 22±7 4.8± 1.6

89± 13' 112± IS 5.5±1.2 14±4

91± 16' 114±21 5.4± 1.3 15±6 1,278±378' 29±6 O.29±O.09tt

53±8 110±20 5.4± 1.1 15±6 647±197 25±5 0.23±0.10 745±206 17S±65 24±6 4.S±3.2

59±10 122±21 5.5± 1.0 16±6 659±217 27±6 0.26±0.09 697±175 188±65 8.2± 10 4.2±2.0

88±S' 128±15 5.9±1.6 19±12*· 1,092 ± 337' 32±9*· 0.25±0.08 803±227 197±67 106±I00tt 3.8±2.0

89±13' 121±14 5.3±1.3 17±7 1,235±396' 32±6·· 0.25±0.06 743±208 186±51 107± 125 3.8±3.0

1,150±~

28±5 0.28±0.10 840±225 232 ± 85tt 153±51' 4.4±1.8

836±91Yl

235±74tt 189 ± 521 2.9±0.8**

·CI = cardiac index; HR = heart rate; IDol = oxygen delivery; IVo. = oxygen uptake; MBP = mean blood pressure; MPAP = mean pulmonary artery pressure; O. ext = oxygen extraction; PCWP = pulmonary capillary wedge pressure; SYRI = systemic vascular resistance index.

tSixteen patients randomized to receive norepinephrine. iFifteen patients who responded to norepinephrine (stabilization and after 6 h). §Sixteen patients randomized to receive dopamine. Irren patients who did not respond to dopamine, 25 p.glkglmin, and subsequently received norepinephrine (stabilization and after 6 h). 'p
difference was observed between the two groups with regard to hemodynamic and metabolic parameters (baseline values). With the use of dopamine, 10 to 25 JLglkglmin, only 5 of 16 patients (31 percent) were successfully treated and fulfilled the therapeutic goals (Table 3) as compared with 15 of 16 patients (93 percent) with norepinephrine (p
These two patients died within a few hours of intractable septic shock despite the addition of epinephrine (5 J'glkglmin). Ten of the 11 patients who did not respond to dopamine, 25 J'glkglmin, were successfully treated with the addition of norepinephrine (1.7 ± 1.8 JLglkglmin) (Table 2). In patients who received norepinephrine first, there were significant increases in MB~ SYRI, IVo2 , and urine How (Table 2). These changes

were maintained over 6 h. A significant decrease in

blood lactate levels was also observed (Table 2). In the

Table 3-Hemodynamic and Metabolic DtJtIJ of the Reapondera (Five lbtienta, 10 to 25 p.gIkglminJ and the Ncmraporatkn (Ten lbtienta, 25 p,g/ldmitaJ to Doparnme* Before Dopamine

MB~mmHg

HR, beat/min CI, Umin/ml PC~mmHg

SYRI, dyn.secJcm5.m1 MPA~mmHg

0. ext

roe, mVmin/m

l

rve; ml/min/m"

Urine output, mllh Lactate, mmoVL

Responders (n = 5)

Nonresponders (n = 10)

54±4 110±20 5.8±1 14±3 642± 147 24±6 O.19±0.06 932± 110 169±71 2O±2 4.7±2.2

51±10 109±IS 5.0±1.1 16±7 601± 197 25±4 0.26±0.09 659±182i 182±65 17±4 4.9±3.7

Dopamine, 10 to 25 ..,glkglmin

..

Responders (n=5)

Responders + 6 hours (n=5)

Dopamine, 25 p.glkWmin, Nonresponders (n = 10)

94±12t 117± 14

96±5t 110± 17 6.1±1.3 15±5 1,270±35Ot 28±9 O.20±O.09 947 ± 205 193±51 196±36t 2.5±1.1t

59±10 122±23 5.5±1 19±411 659±217 28±6 0.26 ± 0.02 697± 175 188±65 8.2± 10 4.2±2.0

6.8±2.1i

19±6§ 1,003±455t 36±7J1 0.21±O.05 1,052±288 221±54 202±25t 4.3±2.15

·CI = cardiac index; HR = heart rate; IDo. = oxygen delivery; IVo. = oxygen uptake; MBP = mean blood pressure; MPAP = mean pulmonary artery pressure; 0. ext = oxygen extraction; PCWP = pulmonary capillary wedge pressure; SVRI = systemic vascular resistance index. tp<0.01 vs "before dopamine."

1828

NoI8pinephrtne or Dopemine in S8pIic Shock? (Martin et 81)

10 patients who did not respond to dopamine, 25 fLW kg/min, and remained markedly hypotensive and oliguric, a similar pattern of evolution was observed (Table 2) when norepinephrine was added. A significant increase in MB~ SVRI, MPA~ PCW~ and urine How was observed, but no signi6cant decrease in blood lactate levels was seen during the study period. In this group of patients, IV0 2 did not change. Table 3 shows the hemodynamic and metabolic data of the 5 patients successfully treated with dopamine, 10 to 25 fLglkWmin. Significant increases in MB~ SVRI, MPA~ PCW~ and urine How were observed. No change in ID02 and IV0 2 was noted. After 6 h of therapy, increases in MB~ SVRI, and urine How were maintained, but MPAP and PCWP returned to baseline values. A significant decrease in blood lactate levels was observed. At the time of inclusion in the study no difference was seen between responders and nonresponders to dopamine with the exception of IDo2 which was greater in the responders (Table 3). Fifteen patients were discharged from the hospital; 9 were primarily given norepinephrine, and 6 were given dopamine. DISCUSSION

The main result of the present study is that, at the dosages tested, norepinephrine was more efficient and reliable than dopamine to reverse the hemodynamic abnormalities seen in hyperdynamic septic shock. Norepinephrine was also capable of being active when high-dose dopamine (25 ...,glkglmin) failed. The traditional treatment of hemodynamic abnormalities of septic shock includes restoration of intravascular volume by Huid infusion and the use of adrenergic drugs if hypotension persists despite adequate volume resuscitation. Dopamine is the most common first choice and its use has been widely advocated. However, several studies have shown that an adequate tissue perfusion pressure cannot be obtained in many patients with the use of dopamine, even at doses as high as 80 ...,glkglmin. 17• 19 In these studies, norepinephrine was found to be beneficial, with improvement in arterial blood pressure, urine Ho~ oxygen delivery, and consumption. However, excessive vasoconstriction with impaired tissue oxygenation is a potential risk when using norepinephrine. To avoid such a deleterious effect, it has been suggested that the rational use of norepinephrine should be based not only on the reversal of hypotension, but also on the achievement of appropriate physiologic end-points on D02 and V0 2 . m ,21 Therapeutic goals and physiologic end-points used in the present study were defined from values previously obtained in survivors of lifethreatening critical illnesses. 22-25 The aim of therapy was to achieve and maintain optimal hemodynamic and oxygen metabolism patterns and, at the same

time, to restore a normal tissue perfusion pressure. The attempt to normalize blood pressure at the expense of CI and D02 , by using high doses of vasopressors, leads to poor survival.P Restoring and maintaining high CI values are not sufficient per se since survivors and nonsurvivors of septic shock may have a normal or high CI even within a few hours of death.~,28 However, previous studies have suggested that maintaining a high CI may be an important goal of therapy since patients who eventually died were reported to exhibit evolution from a hyperdynamic to a hypodynamic state.29-37 To fulfill the therapeutic goals, fluid infusion was selected as the first priority in order to correct blood volume defect. Following volume loading, the patients had high CI and low SVRI, a hemodynamic profile perfectly suited to the use of a potent vasopressor agent. Norepinephrine was able to reverse hemodynamic abnormalities in 93 percent of the patients and dopamine in only 31 percent. Vasopressor infusion should not be considered in patients with high SVRI since elevated cardiac afterload obtained by placing a strain on the myocardium could be deleterious in case of severe cardiac dysfunction. This point is crucial: a potent vasopressor such as norepinephrine must be used only to restore normal values of SVRI and/or systemic arterial blood pressure in patients with severe and documented vasodilation. Although there are some methodologic problems with the use of SVRI as the sole measurement of peripheral resistance.P it was found in the present study that adjusting vasopressor infusion rate according to this parameter was beneficial. Potentially deleterious effects of vasoconstriction were avoided as shown by the improvement in urine output and blood lactate levels. Other studies have demonstrated the beneficial effects of norepinephrine on renal function during septic shock. 17- 19 ,33,34 In patients with hypotension and hypovolemia, eg, during hemorrhagic shock, the use of vasopressor should be avoided for the following reasons: despite the constant improvement in blood pressure, renal blood flowdecreases and renal vascular resistance rises." The situation is different in hyperdynamic septic shock. It is speculated that urine flow decreases mainly as a result of lowered glomerular perfusion pressure. Since norepinephrine has a greater effect on efferent than on afferent arteriolar resistance" and increases the filtration fraction, normalization of renal vascular resistance could effectively reestablish urine How Schaer et al36 have demonstrated that when CI is normal or elevated, norepinephrine increases renal vascular resistance but renal blood Howremains stable or even increases. The increase in urine output observed in most of the study patients could also be explained by a decrease in antidiuretic hormone release which, through different mechaCHEST I 103 I 6 I JUNE, 1993

1829

nisms, favors water retention." Cardiac and sinoaortic baroreceptors are sensitive to pressure and in case of low intravascular pressure they induce an activation of the sympathic system and an increase antidiuretic hormone secretion." Restoration of adequate systemic and central pressures in patients with septic shock probably resulted in an inhibition of vasopressin secretion. 39 Given the positive correlation between V0 2 and survival4-9.40-42 in septic shock, increasing and maintaining Do2 , even to supranormal values, is one of the major goals of therapy In the present study, the patients receiving norepinephrine exhibited an increase in Vo2 , unaccompanied by an increase in Do2 • This could be a direct effect of the adrenergic drug on the oxidative metabolism." However, the decrease in lactate blood levels observed in the present study does not support this hypothesis, and oxygen was preferentially used in the mitochondria, as the affinity of the extramitochondrial oxidase system is lower than the mitochondrial oxygen transport chain (cytochrome A3).44 An explanation for the increase in V0 2 and the decrease in lactate levels could be the correction of splanchnic ischemia with an efficient hepatic lactate uptake. Indeed, increase in splanchnic blood Howhas been demonstrated in patients with hyperdynamic septic shock after the use of norepinephrine. 45 Another explanation is that under the influence of norepinephrine, vascular reactivity was restored and blood How was directed toward the areas of greatest oxygen demand, thus optimizing oxygen extraction..f6 In conclusion, this study confirms that norepinephrine can be useful to reverse the hemodynamic and metabolic abnormalities of severe hyperdynamic septic shock states. At the doses tested, norepinephrine was found to be more effective and reliable than dopamine for that purpose and can be used even when the latter has failed. In the study patients, norepinephrine fulfilled the therapeutic goals in 93 percent of the patients, and dopamine fulfilled the goals in only 31 percent (p
4 5 6

7 8 9 10 11 12 13 14 15

16 17 18 19 20 21

min/m"),

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