Effects of N-acetylcysteine in endotoxic shock

Effects of IV-Acetylcysteine in Endotoxic Shock

Jan Bakker, Haibo Zhang, Michel Depierreux, Sweder van Asbeck, and Jean-Louis Vincent

Purpose: The release of oxygen-free radicals has been implicated in both peripheral vascular and myocardial alterations of septic shock. N-Acetylcysteine (N-AC), a substrate for the production of glutathione, has potent antioxidant effects. As a nitrosothiol, it may also improve capillary blood flow. We studied the effects of N-AC in a dog model of endotoxic shock. Methods: Ten pentobarbital-anesthetized, mechani- cally ventilated dogs were randomly assigned to re- ceive either N-AC (150 mg/kg loading dose in 1 hour, followed by 20 mg/ kg . h maintenance dose) or D5W. After the loading dose, each dog received 3 mg/kg Escherichia co/i endotoxin intravenously. After 30 minutes, saline infusion was started to restore and maintain baseline filling pressures. Results: The loading dose of N-AC increased Do2 significantly (from 661 f 54 to 914 f 190 mL/min, P < .05), but Vo2 remained stable. After the administra-

S EPTIC SHOCK IS characterized by an increase in oxygen demand caused by the

host’s response to infection. Despite an usually normal or increased oxygen delivery (Do*), oxygen consumption (Vo,) may be dependent on Do, (supply dependency), and the blood lactate levels may be increased, suggesting the presence of cellular hypoxia.4 Myocardial de- pression may limit the increase in Do, necessary to meet the elevated oxygen demand.15 Also, an impairment of the oxygen extraction capabilities of the tissues21,30 can significantly contribute to limit oxygen availability to the cells. Microvas- cular abnormalities caused by decreased vascular tone, obstruction by cellular aggregates, release of various mediators, and subsequent alterations in endothelial cell function with edema formation have all been implicated in the pathogenesis of this oxygen extraction de- fect.”

Oxygen-free radicals have been implicated in the loss of vascular control, the alterations in

From the Departments of Intensive Care and Pathology, Erasme University Hospital, Free University of Brussels, Bel- gium, and the Department of Internal Medicine, University Hospital Utrecht, University of Utrecht, Netherlands.

Received December 29, 1993; accepted August 2, 1994. Address reprints requests to Jean-Louis Vincent, MD, PhD,

Department of Intensive Care, Erasme University Hospital, Route de Lennik SOS, B-1070 Brussels, Belgium.

Copyright 0 1994 by W B. Saunders Company 0883-9441/94/0904-0003$05.00~0

236

tion of endotoxin, fluid challenge restored cardiac output to baseline, in both groups. Hemoglobin and, thus, Do2 were slightly lower in the N-AC-treated dogs, but Vo2 was similar in both groups. At the end of the study, 02ER was significantly higher in the N-AC- treated dogs than in the control dogs. Blood lactate levels fell more rapidly in the N-AC dogs than in the control dogs. Blood lactate levels returned to normal in the N-AC dogs but not in the control dogs. Tumor necrosis factor (TNF) also decreased significantly in the N-AC dogs but remained elevated in the control dogs. Conclusion: These data indicate that N-AC administration in endotoxic shock is well tolerated, may increase oxygen availability to the tissues, and is associated with an attenuation of TNF release. Copyright 0 1994 by W. B. Saunders Company

vascular permeability, and the development of myocardial dysfunction during septic shock.“J8 Glutathione is a natural intracellular antioxidant, whose levels have been found to be decreased in septic shock.12,24 Furthermore, glutathione depletion has been associated with tissue injury and increased mortality.19 N- Acetylcysteine (N-AC), a substrate for glutathione synthesis,28 can have important antioxidant effects.5 N-AC may also enhance the activity of endothelium-derived-relaxing factor (EDRF) and thereby improve microvascular blood flow.” Thus, N-AC could have protective effects during endotoxin shock. Experimentally, N-AC has been shown to decrease neutrophil and platelet aggregating activity, attenuate pulmonary hyper- tension, and vascular permeability.5,7J4 In a porcine model of endotoxin shock, N-AC increased cardiac output and Doz.lS In a recent experimental study, Zhang et al29 found that after endotoxin administration in dogs, N-AC could improve the oxygen extraction capabilities when blood flow was acutely reduced.

Before embarking into a clinical trial evaluat- ing the effects of N-AC in septic shock in humans, we sought to define the effects of N-AC on an animal model more closely mimicking human septic shock. For this purpose, we selected a dog model of endotoxic shock resusci- tated with generous fluid infusion because this model is characterized by arterial hypotension, low systemic vascular resistance, and altered

JournalofCriticalCare, Vol9, No 4 (December), 1994: pp 236-243

N-ACETYLCYSTEINE IN ENDOTOXIC SHOCK 237

oxygen extraction.” The primary questions asked were whether the vasodilating properties of N-AC would be well tolerated in these conditions and whether N-AC could be associated with an increased oxygen availability to the tissues. We also sought to confirm whether N-AC could reduce the tumor necrosis factor (TNF) release in these endotoxic shock conditions.

MATERIALS AND METHODS

The experiments were conducted according to the guide- lines of the National Institutes of Health. The study included 10 mongrel dogs (weight 23 2 5 kg) anesthetized with pentobarbital(25 mgikg bolus followed by a 4 mgikglh infusion). After endotracheal intubation, mechanical ventilation was started on control mode with air (Elema 900 B; Siemens, Solna, Sweden) with a respiratory rate set at 12 breathsimin and a tidal volume adjusted to maintain Pacox between 30 and 40 mm Hg. Muscle paralysis was obtained by pancuronium bromide, administered at an initial dose of 0.1 mgikg and subsequent doses of 2 mg every hour.

Electrodes were attached for heart rate monitoring. A capnometer (model 47210 A; Hewlett Packard, Palo Alto, CA) was placed on the respiratory circuit for Pcoz monitoring. Exhaled gases were directed through a mixing chamber for sampling. Expired oxygen fraction (Feoz) was measured by a semirapid gas analyzer (model 500D PK, Morgan Co. Chatham, England). A pulmonary artery catheter (Swan- Ganz catheter, model 93A-431H-7.5F; Baxter-Healthcare. Irvine, CA) was inserted via the right jugular vein. An arterial catheter (16G 8: Becton Dickinson, Rutherford, NJ) was inserted into a femoral artery. Similar catheters were inserted in the peripheral limb veins for fluid and drug administration. During instrumentation, dogs received 0.9% saline (1 ml/kg/h).

Dogs were randomly divided into two groups. After baseline measurements, N-AC dogs (n = 5) received N-AC dissolved in D5W (60 mg/mL) as a loading dose of 150 mgikg for 1 hour followed by a maintenance dose of 20 mgikgih. Control dogs received D5W alone at equal vol- umes. Thirty minutes after the end of the loading dose, measurements were repeated, and all dogs received 3 mg/kg of Eschetichia coli endotoxin (055 B5; Difco, Detroit, MI), slowly injected intravenously in 2 minutes. The dogs were observed for 30 minutes before a 30-minute fluid challenge with 0.9% saline was performed to restore baseline filling pressures. Thereafter, fluid administration was adapted throughout the experiment to maintain pulmonary artery balloon occluded pressure at baseline level. Temperature of the animal was kept constant using a warming blanket and humidified heated gases.

Intravascular pressures, cardiac output, arterial and mixed venous blood gases, expired oxygen concentration, end-tidal CO? concentration, and minute ventilation were measured at baseline, and every 30 minutes thereafter for 5 hours. Intravascular pressures were measured by pressure transduc- ers (P 23; Gould, Oxnard, CA) and continuously recorded along with heart rate (Recorder 7404; Hewlett Packard,

Waltham, MA). The zero pressure level was set at the midchest level of the animal. Arterial pressure, pulmonary artery pressure, pulmonary artery balloon occluded pressure, and right atria1 pressure were measured at cnd- expiration from the paper trace. Cardiac output was measured by the thermodilution technique (REF-1 computer; Baxter Healthcare) by serial (three to five) injections of 5 mL of iced ( < 2°C) D5W started at end-inspiration. After each cardiac output measurement, arterial and mixed venous blood were obtained to measure blood gases and hemoglobin. Arterial blood lactate, white blood cell count. platelets, coagulation parameters (aPTT. PT), fibrinogen. and TNF levels were measured at baseline and every 30 minutes thereafter. Blood gases were determined with an automated analyzer (ABL 2; Radiometer. Copenhagen. Denmark). Hemoglobin saturations were calculated with a nomogram.20 Blood lactate concentrations were measured enzymatically with an automated system (Kontron, Basel, Switzerland). TNF levels were measured in serum using the murine L-929 fibroblast cytotoxicity assay (L-cell assay). L-929 cells were placed in culture (73X, 5% CO?) in 96well tissue culture plates (Nunc, Roskilde, Denmark) at a density of 4 x 10J cells per well. Dulbecco’s modified Eagle’s medium (DMEM) supplemented with 10% fetal calf serum and gentamicin (10 pg/mL) was used as culture medium. After 4 hours of incubation, standard recombinant human TNF (rHuTNF), and serum were added in various concentrations in a total volume of 100 uL per well. This was followed by the addition of 100 JLL. actinomycin D (final concentration 1 kg/mL). After an incubation period of 20 hours and fixation with glutaraldehyde (L&3%), cells were stained with methylene blue (0.05%) for 30 minutes. The TNF unit per milliliter represents the reciprocal of the TNF dilution causing 50% cytotoxicity under the described conditions. The sensitivity range of this assay was IO to 100 pg/mL as determined by rHuTNF.

After completion of the experiment dogs were killed with potassium chloride and biopsies were immediately taken from the lung (right lower lobe), liver (right lobe), spleen, small intestine (30 cm from the flexura duodenojejunalis), large intestine (colon ascendens), right kidney, and mvocar- dium (left and right ventricle). Tissue blocks were fixed overnight in 4% formalin imbedded in parafhn and rou- tinely processed for optical observation. Sections were stained with hematoxilin and eosin. Pathological examination was performed blindly (M.D.). Lesions were scored on a scale from 0 (no lesions) to 4 (severe lesions) and averaged for each group.

Stroke volume, systemic vascular resistance. pulmonary vascular resistance, left ventricular stroke work (I.VSW), and Do? were calculated by standard formulas. Voz was calculated from the measured expired oxygen concentration and minute ventilation. using the appropriate mass halance equation.’ 02ER was calculated as the ratio of VCI: over DO:.

Statistical analysis was performed usmg analysts of vari- ance for repeated measurements (ANOVA) with Newman- Keuls and Dunnett adjustment. Results from pathological examination were analyzed by paired Student‘s r-test. A P value less than .05 was considered as statistically significant. All data are presented as mean ? SD.

238 BAKKER ET AL

RESULTS

The loading dose of N-AC had no significant effects on mean arterial pressure (MAP) and filling pressures, but increased cardiac output by 25% (from 4.0 f 0.7 to 5.0 f 0.8 Llmin, NS, Fig 1). LVSW increased nonsignificantly (Table 1). DO2 increased from 661 k 54 to 914 2 190 mL/min (P < .OS) but Vo? remained stable

I

Endotoxin administration resulted in a significant decrease in MAP in both groups, which persisted throughout the experiment. Cardiac output decreased transiently in both groups but returned to baseline levels with fluid challenge (Fig 1). N-AC-treated dogs had a slightly lower hemoglobin and thus Do, (NS, Table 1 and Fig 2). As Voz was similar in both groups, 02ER

(Fig 2). was higher in the N-AC dogs than in control

I 3 mgkg endotoxin

160-

140-

120-

I" 1 oo-

E 80-

9 60-

40-

20-

O-

t N-AC loading 1 MAINTENANCE CCSE 1

FC 1 N&l 0.9% to maintain PAW at beslim

I I I I I I I I I I I

0 30 60 90 120 150 180 210 240 270 300

6

5

C .-

3 4

8

3

2

Time min

Fig 1. MAP and cardiac output (CO) in the control group (0) and N-AC group (0). N-AC load-

J. ing, infusion of N-AC loading

I I I I I 1 I I I I 1 dose or D5W alone; maintenance

0 30 60 90 120 150 180 210 240 270 300 dose, infusion Of mAc mainte-

Time min nance dose or D5W alone. *P < .05 versus baseline.


Table 1. Selected Hemodynamic and Laboratory Data in 10 Dogs -...- _

Time (Min)

T=O T = 90 T= 120 Variable Group Baseline T = 60 Post EDTX Post FC T= 180 T = 240 T 300

____ Temperature "C Control 38.1 % 0.6 38.0 k 0.6 38.5 + 0.8 38.3 f 0.9 38.2 k 1.0 38.3 r 1.0 38.4 f 1.0

N-AC 38.5 f 0.5 38.4 2 0.7 38.6 k 0.7 38.3 + 0.6 38.3 k 1.1 38.1 t 1.2 38.1 + 1.2

Control 151 2 21 160 5 10 149 -t 14 152 t 15 150 r 11 147 2 16 131 + 27 Heart rate (beats/min) N-AC 161 '- 31 170 + 35 171 5 22 170 + 27 168 2 23 169 -+ 22 166 2 76

Mean arterial pres- Control 128 f 14 128 -t 16 75 2 34t 72 f 27t 78 t llt 89 t 12f 90 +- !6* sure (mm Hg) N-AC 124 + 24 128 ? 23 78 + 30" 92 + 25 87 z!r 26 94 t 20 96 t '6

Mean pulmonary arte-

rial pressure (mm Control 12.9 * 2.9 14.3 + 3.1 14.5 + 5.0 14.0 + 2.5 14.5 2 3.9 16.8 + 2.2 17.9 + 3.7 Ml N-AC 12.1 + 2.0 14.6 I+_ 2.8 15.9 t 5.9 13.9 + 4.9 14.0 k 2.3 15.5 + 2.5 14.7 t 2.1

Pulmonary artery occlusion pressure Control 3.4 + 0.5 3.1 f. 0.5 2.4 -t 0.9 3.2 -t 0.3 2.9 t 0.7 3.9 k 0.7 :3.6 + 0.5

(mm Hg) N-AC 3.2 -+ 0.7 3.3 2 0.8 2.2 + 0.9 3.3 2 1.4 2.8 + 1.0 3.4 +- 1.1 3.5 IT 1.0 Right atrial pressure Control 1.5 + 0.5 1.9 f 0.7 1.3 i 1.0 1.8 + 0.8 1.7 5 0.7 2.0 + 1.2 2.6 + 0.9

(mm Hgl N-AC 1.6 c 0.9 1.7 + 1.1 1.1 -c 1.1 1 .o 2 0.7 1.5 5 0.8 2.0 + 0.7 2.4 i 0.8

Left ventricular stroke Control 49.7 & 18.4 44.6 r 11.7 20.3 f 14.0 26.0 t 16.1 25.8 2 6.2 32.6 ? 6.5 36.0 t 14.4 work (g m/beat) N-AC 44.4 2 19.3 52.3 r 18.0 16.6 +- 5.8 28.5 + 10.0 26.2 k 10.0 29.6 -+ 7.3 26.9 2 4.9

Systemic vascular

resistance (dyn Control 2,433 + 378 2,520 2 708 2,061 + 735 1,403 + 366 1,656 ? 374 1,745 ? 448 1,832 1 326 sec/cm5) N-AC 2,429 -t 313 2,055 + 358 2,357 IC_ 1,422 1,871 2 573 1,810 + 492 1,929 2 687 2,218 z? 850

Control 13.8 + 1.2 14.7 + 1.6 16.7 2 2.1 16.3 + 2.4 16.3 2 2.7 15.8 k 3.0 15.9 z 2.8

Hemoglobin (mg/dL) N-AC 12.6 -t 1.1 14.3 5 1.4 16.4 r 1.6t 15.3 k 1.1* 14.3 i 1.1 14.0 ir 1.0 14.4 L 1.4 Control 7.39 ? 0.05 7.34 + 0.06 7.20 c 0.10" 7.19 r 0.07* 7.20 2 0.08* 7.19 + O.lO* 7.21 I 0.09*

Arterial pH (U) N-AC 7.40 k 0.03 7.36 k 0.05 7.19 + 0.09* 7.18 + 0.09* 7.18 + O.ll* 7.20 2 0.09* 7.22 -f 0.08'

Arterial oxygen pres- Control 108 + 3 104 c 7 98 2 6 98 c 5 96 2 6 96 i 8 96 ?~ 10 sure (mm Hg) N-AC 108 -t 1 105 5 5 96 2 8 93+ 13 932 15 942 12 98 t 9

Mixed venous oxygen Control 43 + 8 46 2 8 42 t 9 50 k 7 51 26 50 + 5 49 t 7 pressure (mm Hg) N-AC 43 2 5 48 c 4 41 k 7 46 t 10 47 k 7 48-+5 47 ? 6

-.-- Note: Control, dogs receiving D5W only (n = 5); N-AC, dogs receiving N-AC (n = 5): Post EDTX, post endotoxin administration; Post

FC, post fluid challenge.

*P < .05 v baseline (T = 0). tP i .Ol Y baseline (T y 0).

dogs (Fig 2). At the end of the study (T = 300), 02ER was 26.5% + 2.8% in the N-AC group but 20.4% +- 5.0% in the control group (P < .OS). Both groups developed metabolic acidosis but blood lactate levels fell more rapidly in N-AC dogs than in the control dogs. Blood lactate levels returned to normal in the N-AC dogs, but not in the control dogs (Fig 3).

Some TNF activity was initially found in all animals, after handling and instrumentation. TNF levels almost tripled after endotoxin administration. Subsequently, they decreased dramatically in N-AC dogs but not in control dogs (Fig 3). No significant differences were found in white blood count, platelet count, coagulation parameters (aPTI?, PT), and fibrinogen levels between both groups (data not shown). Patho- logic examination revealed only mild alterations, but no significant differences between

the two groups. Congestion was present in all organs examined (Table 2).

DISCUSSION

The present endotoxic shock model, characterized by arterial hypotension in the presence of a well-maintained cardiac output after fluid administration, reproduces fairly well the hemodynamic alterations associated with septic shock in humans. The study showed that pretreatment with N-AC had no effect on arterial pressure. N-AC-treated animals had a more rapid decine in blood lactate levels associated with a higher oxygen extraction ratio as compared with the control dogs, suggesting that cellular oxygen availability was improved by N-AC. Although other mechanisms than tissue hypoxia may be implicated in the increase in blood lactate levels after endotoxin administration,‘h we believe

+

3 mgkg endotoxin

-5 800- E

Li E 600- N

B 400-

200 1

200-

175-

-; 150-

Li E c-4 125-

s

IOO-

N-AC loading 1 MAINTENANCE DOSE 1 FC 1 NaCl 0.9% lo malntaln PAOP at basehe 1


0 30 60 90 120 150 180 210 240 270 300 Time min

0 30 60 90 120 150 180 210 240 270 300 45 Time min

1 40-

IO-

5-

O- I I I I I I I I I I 1

0 30 60 90 120 150 180 210 240 270 300

Time min

Fig 2. Oxygen delivery (D02), oxygen consumption (Vo,), and oxygen extraction ratio (02ER) in the control group (0) and N-AC group (0). N-AC loading, infusion of N-AC loading dose or D5W alone; maintenance dose, infusion of N-AC maintenance dose or D5W alone. *P < .05 versus baseline; l P e .05 versus control group.


3 mslks endotoxin

6

5 1 4 1 4-

$ 2 3-

cu z 4 2-

l-

O-

Fig 3. Blood lactate levels and I-

tumor necrosis factor (TNF) in the control group (0) and N-AC group (@). N-AC loading, infusion of N-AC loading dose or D5W alone; maintenance dose, infusion of N-AC maintenance dose or D5W alone. “P c .05 versus baseline; @P e .05 versus T = 90: l P e .05 versus control group; V c .05 versus T = 120.

1007

10:

I‘

N-AC loading 1 MAINTENANCE DOSE I

FC 1 NaClO.9% to mlninin PAOP at besellna

I 1 I I 1 I I I I I I

0 30 60 90 120 150 180 210 240 270 300

Time min


0 30 60 90 120 150 180 210 240 270 300

Time min

that an improvement in oxygen availability in study did not allow us to specifically study the the cell remains the most likely mechanism to effects of N-AC on oxygen extraction capabili- explain the more rapid decline in lactate levels ties during endotoxic shock. However, these in the N-AC-treated animals. In addition, a observations are consistent with the results of a more rapid decrease in lactate levels in septic recent study from our group, using a different shock has been associated with lower morbidity dog model in which an acute reduction in blood and mortality rates. 2,27 The design of the present flow was imposed by pericardial tamponade.2y

242 BAKKER ET AL

Table 2. Pathological Examination in 10 Dogs one may increase TNF production,i6 whereas TNF by itself can also decrease intracellular glutathione levels.‘O Thus, by repleting intracellular glutathione levels, N-AC may break a vicious circle in which the release of oxygen-free radicals increase the TNF production, which in turn activates the release of oxygen-free radicals. In our study, TNF levels rapidly decreased only in N-AC dogs. The TNF levels were initially increased after surgical instrumentation, as it has been observed before.’ Because we did not heat the serum before the TNF measurement, other substances present in the serum could have influenced our TNF-bio-assay. How- ever, TNF levels increased markedly after endotoxin administration in both groups but decreased dramatically only in the N-AC-treated animals. These results are in agreement with two other recent studies indicating that pretreatment with N-AC can significantly inhibit the endotoxin-induced TNF production.16J9

Organ and Lesions Control N-AC (n = 5) In = 5) P Value

Heart

Inflammation

Congestion/edema Lung

Alveoli

Septa Bronchioles

Congestion/edema Liver

Sinus

Hepatocytes Kupffer cells

Congestion/edema Spleen

White pulp

Red pulp Congestion/edema

Kidney

Glomeruli Tubules

Congestion/edema GI Tract

0.2 2 0.45

1.0 k 1.0

0.2 2 0.5 0.4 2 0.6

0

1.2 k 0.8

1.2 t 0.5 0

0.2 2 0.5 2.6 2 1.8

0

1.0 + 0.0 1.0 +- 0.0

0 0

0.4 2 0.6 0

0 0.2 zk 0.5

0 0.4 + 0.6

0

1.6 r 0.9

0.6 k 0.9 0

0.2 k 0.5 3.4 + 1.1

0

1.0 t 0.7 1.0 + 0.0

0 0

0.4 zi 0.6 0

NS NS

NS NS

NS

NS

NS

NS

NS

NS

NS

Notes: Lesions were scored on a scale from 0 (no lesions) to 4 (severe lesions) and averaged for each group.

Abbreviations: GI Tract, gastrointestinal tract; NS, not signifi-

cant; Control, dogs receiving D5W only; N-AC, dogs receiving

N-AC.

In that study, N-AC increased the oxygen extraction capabilities after endotoxin administration, as indicated by a reduction in critical Do2 and an increase in critical 02ER.29

Oxygen-free radicals have also been implicated in the sepsis-related myocardial depres- sion and N-AC could thus exert some protective effects on myocardial function in these conditions,1s,29 but this was not observed in the present study.

Several mechanisms could account for the beneficial effects of N-AC in endotoxic shock. First, by restoring intracellular glutathione levels, N-AC can exert important scavenging effects on oxygen-free radicals, which could other- wise disrupt cellular function, either directly or via generation of lipid peroxidation. Glutathi- one peroxidase can reduce reactive oxygen inter- mediates (H202) whereas other membranous and cytosolic glutathione-dependent enzymes can inhibit lipid peroxidation Oxygen-free radical formation can activate the inflammatory response and increase the TNF release,” so that N-AC could exert important anti-inflammatory effects. Depletion of intracellular glutathi-

Second, N-AC could also improve the oxygen availability of the cells by its effects on microvascular blood flow. In the present study, the vasodilating effects of N-AC were shown by an increase in cardiac output before endotoxin administration. The slightly lower hemoglobin level in the N-AC-treated dogs may be related to a more profound vasodilation and subsequent hemodilution in these dogs.14 These effects could be mediated by the action of EDRF because sulfhydryl compounds can promote the generation of nitric oxide and oxygen-free radicals can abolish the biological activity of EDRF.8 N-AC can also inhibit platelet and granulocyte aggregation in septic conditions.13

Finally, the anti-inflammatory and antioxidant effects of N-AC may prevent increased microvascular permeability and, thus, limit edema formation that could compress the micro- vasculature and increase the diffusion distance of oxygen from the capillaries to the cells.’ However, in our acute study, pathologic examination of the organs studied showed moderate congestion and edema, in the two groups of animals. Hence, an effect of N-AC on microvascular permeability did not play a significant role in our short term experiments.

The effects of N-AC administration have been recently reported in patients with acute respiratory failure or sepsis.2Z,25 Spies et a122


recently reported that N-AC could also increase clinical trials with N-AC in patients with severe Do2 and Vo, and increase gastric intramucosal sepsis and septic shock. pH in septic patients. The present observations show that N-AC is well tolerated and may ACKNOWLEDGMENT improve tissue oxygenation in endotoxin shock. The N-acetylcysteine was kindly supplied by Inpharzam These observations should stimulate further (Milan, Italy).

REFERENCES

I. Ayala A, Kisala JM, Felt JA, et al: Does endotoxin tolerance prevent the release of inflammatory monokines (Interleukin 1, Interleukin 6, or tumor necrosis factor) during sepsis. Arch Surg 127:191-197,1992

2. Bakker J, Coffernils M, Leon M, et al: Blood lactate levels are superior to oxygen derived variables in predicting outcome in human septic shock. Chest 99:956-962, 1991

3. Bakker J, Vincent JL: The effects of norepinephrine and dobutamine on oxygen transport and consumption in a dog model of endotoxic shock. Crit Care Med 21:425-432, 1993

4. Bakker J, Vincent JL: The oxygen supply dependency phenomenon is associated with increased blood lactate levels. J Crit Care 6:152-159, 1991

5. Bernard GR, Lucht WD, Niedermeyer ME, et al: Effect of N-acetylcysteine on the pulmonary response to endotoxin in the awake sheep and upon in vitro granulocyte function. J Clin Invest 73:1772-1784,1984

6. Gibson DD, Hawrylko J, McCay PB: GSH-dependent inhibition of lipid peroxidation: Properties of a potent cytosolic system which protects cell membranes. Lipids 20:704-711,1985

7. Groeneveld AB, Den Hollander W, Straub J, et al: Effects of N-acetylcysteine and terbutaline treatment on hemodynamics and regional albumin extravasation in porcine spetic shock. Circ Shock 30:185-205, 1990

8. Gryglewski RJ, Palmer RM, Moncada S: Superoxide anion is involved in the breakdown of endothelium-derived vascular relaxing factor. Nature 320:454-456,1986

9. Hill RW: Determination of oxygen consumption by use of the paramagnetic oxygen analyzer. J Appl Physiol 33:261-263,1972

10. Ishii Y, Partridge CA, Del Vecchio PJ, et al: Tumor necrosis factor-[67od] a-mediated decrease in glutathione increases the sensitivity of pulmonary vascular endothelial cells to H202. J Clin Invest 89:794-802, 1992

11. Jackson CV, Mickelson JK, Pope TK, et al: 02 free radical-mediated myocardial and vascular dysfunction. Am J Physiol2Sl:H1225-H1231,1986

12. Keller GA, Barke R. Harty JT, et al: Decreased hepatic glutathione levels in septic shock. Arch Surg 120:941- 945,1985

13. Lucht WD. English DK, Bernard GR, et al: Preven- tion of release of granulocyte aggregants into sheep lung lymph following endotoxemia by N-acetylcysteine. Am J Med Sci 294:161-167, 1987

14. Modig J, Sandin R: Haematological, physiological and survival data in a porcine model of adult respiratory distress syndrome induced by endotoxaemia. Acta Chir Stand 154:169-177,1987

15. Natanson C, Fink MP, Ballantyne HK, et al: Gram- negative bacteremia produces severe systolic and diastolic

cardiac dysfunction in a canine model that stimulates human septic shock. J Clin Invest 78:259-270. 1986

16. Peristeris P, Clark BD, Gatti S, et al: N-acetylcysteine and glutathione as inhibitors of tumor necrosis factor production. Cell Immunol 140:390-399, 1992

17. Pogrebniak HW, Merino MJ. Hahn SM, et al: Spin trap salvage from endotoxin: The role of cytokine down- regulation. Surgery 112:130-139,1992

18. Prasad K, Kalra J, Chaudhary AK, et al: Effect of polymorphonuclear leukocyte-derived oxygen free radicals and hypochlorus acid on cardiac function and some bio- chemical parameters. Am Heart J 119:538-550, 1990

19. Robinson MK, Rounds JD, Hong RW. et al: Glutathi- one deficiency increases organ dysfunction after hemor- rhagic shock. Surgery 112:140-149, 1992

20. Rossing RG, Cain SM: A nomogram relating PO?, pH, temperature and hemoglobin saturation in the dog. J Appl Physiol215:195-201, 1966

21. Samsel RW, Nelson DP, Sanders WM, et al: Effect of endotoxin on systemic and skeletal muscle 0: extraction. J Appl Physiol65:1377-1382, 1988

22. Spies CD, Reinhart K, Witt I, et al: Influence of N-acetylcysteine on 02 consumptium and gastric intramucosal pH in septic patients. Crit Care Med 21Sl83. 1993 (abstr)

23. Stamler J, Mendelsohn ME, Amarante P, et al: N-acetylcysteine potentiates platelet inhibition by endothelium-derived relaxing factor. Circ Res 65:789-795, 1989

24. Sugino K, Dohi K, Yamada K et al: Changes in the levels of endogenous antioxidants in the liver of mice with experimental endotoxemia and the protective eh’ects of the antioxidants. Surgery 105:200-206, 1989

25. Suter PM, Domenighetti G, Schaller MD, et al: N-acetylcysteine enhances recovery from acute lung injury in man. A randomized, double-blind, placebo-controlled clinical study. Chest 105:190-194,1994

26. Vary TC, Siegel JH, Nakatani T, et al: Effect of sepsis on activity of pyruvate dehydrogenase complex in skeletal muscle and liver. Am J Physiol250:E634-E640. 1986

27. Vincent JL, Dufaye P, Berre J, et al: Serial lactate determinations during circulatory shock. Crit (‘are Med 11:449-451, 1983

28. Williamson JM, Boettcher B, Meister A: Intracellular cysteine delivery system that protects against toxtcity by promoting glutathione synthesis. Proc Nat1 Acad Sci USA 79~6246-6249, 1982

29. Zhang H, Spapen H, Nguyen DN. et al: Protective effects of N-acetylcysteine in endotoxemia. Am J Physiol 266:H1746-H1754, 1994

30. Zhang H, Vincent JL: Oxygen extraction is altered by endotoxin during tamponade-induced stagnant hypoxia in the dog. Circ Shock 40: 168- 176. 1993

Effects of N-acetylcysteine in endotoxic shock

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