hypertonic saline: here we go again?

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ABSTRACTS & COMMENTARY Basic Science Hypertonic Saline: Here We Go Again? Guest Reviewers: M. Kelley Bullard, MD, Kamakshi Raimondo, and Andre R. Campbell, MD, Department of Surgery, University of California San Francisco School of Medicine, San Francisco General Hospital, San Francisco, California HYPERTONIC SALINE RESUSCITATION OF HEMORRHAGIC SHOCK DIMINISHES NEUTROPHIL ROLLING AND ADHERENCE TO ENDOTHELIUM AND REDUCES IN VIVO VASCULAR LEAKAGE. Pascual JL, Ferri LE, Seely AJ, et al. Ann Surg. 2002;236: 634–642. Objective: To compare the effects of resuscitation with hy- pertonic saline versus lactated ringers on vascular permeability after hemorrhagic shock. Design: In vivo, murine model. Setting: McGill University Health Center, McGill Univer- sity, Montreal, Quebec, Canada. Participants: A total of 33 male 25-g to 30-g CD1 mice. Methods: Thirty-three mice were randomized to 1 of 3 groups. 1. Hypertonic saline (HTS) after hemorrhage (12 mice) 2. Lactated ringer (RL) after hemorrhage (12 mice) 3. Sham (9 mice: no hemorrhage, no resuscitation) Hemorrhagic shock was induced by withdrawing blood until a mean arterial pressure of 50 mm Hg was achieved. Hypotension was maintained in the range of 40 to 50 mm Hg by further with- drawals or reinfusions of blood. After 45 minutes of sustained hypotension, the animals were resuscitated using 1 of 2 randomly assigned regimens. The sham group underwent all experimental preparations but was not subjected to hemorrhage or resuscitation. All 3 experimental groups underwent exteriorization of the cremaster muscle for intravital microscopy. Video recordings of each animal’s microvasculature were captured before, during, and after resuscitation to quantify endothelial cell–polymorphonuclear neutrophil interactions. Polymorphonuclear neutrophil rolling, rolling velocity, and PMN adherence were measured at 15-minute intervals for a total of 90 minutes. After completion of video re- cordings, vascular permeability was measured with an injection of fluorescent-labeled bovine serum albumin. Vascular leakage was calculated after 15 minutes by comparing the intensity of fluores- cence of the perivascular space with the vascular space. Postmor- tem, the cremaster muscle was analyzed immunohistochemically for the expression of ICAM-1, an endothelial cell receptor that strongly interacts with PMN integrins. A single investigator graded the intensity of expression of ICAM-1 semiquantitatively. Results: 1. There were no differences between groups in flow mechanics. 2. Hypertonic saline-resuscitated animals displayed roughly half the number of rolling PMNs and roughly one-fourth the amount of total PMN adherence when compared with the RL group. 3. There were no significant differences between the HTS and sham groups. 4. The PMN rolling velocity tended to be greater in both HTS and sham groups compared with RL at all time points after resuscitation. 5. The HTS group displayed 45% less vascular leakage than the RL group. 6. Vascular leakage was slightly higher in HTS than in sham mice. 7. Cremasteric muscle vascular EC expression of ICAM-1 was similar in both HTS and RL animals. 8. Both circulating leukocyte and PMN counts tended to be higher in the HTS group than in both the sham and RL groups. 9. The proportion of circulating leukocytes that were PMNs was similar in all groups. Current Surgery presents a comprehensive review of recent surgical and medical literature for the surgeon who wants to stay well informed in the least amount of time. Our international board of editors selects significant articles to review and provides commentary. The editorial board welcomes suggestions of topics or specific articles from our readers. CURRENT SURGERY • © 2004 by the Association of Program Directors in Surgery 0149-7944/04/$30.00 Published by Elsevier Inc. 247

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ABSTRACTS & COMMENTARY

Basic Science

Hypertonic Saline: Here We Go Again?Guest Reviewers: M. Kelley Bullard, MD, Kamakshi Raimondo, and Andre R. Campbell, MD,Department of Surgery, University of California San Francisco School of Medicine, San FranciscoGeneral Hospital, San Francisco, California

HYPERTONIC SALINE RESUSCITATION OFHEMORRHAGIC SHOCK DIMINISHES NEUTROPHILROLLING AND ADHERENCE TO ENDOTHELIUMAND REDUCES IN VIVO VASCULAR LEAKAGE.Pascual JL, Ferri LE, Seely AJ, et al. Ann Surg. 2002;236:634–642.

Objective: To compare the effects of resuscitation with hy-pertonic saline versus lactated ringers on vascular permeabilityafter hemorrhagic shock.

Design: In vivo, murine model.

Setting: McGill University Health Center, McGill Univer-sity, Montreal, Quebec, Canada.

Participants: A total of 33 male 25-g to 30-g CD1 mice.

Methods: Thirty-three mice were randomized to 1 of 3 groups.

1. Hypertonic saline (HTS) after hemorrhage (12 mice)2. Lactated ringer (RL) after hemorrhage (12 mice)3. Sham (9 mice: no hemorrhage, no resuscitation)

Hemorrhagic shock was induced by withdrawing blood until amean arterial pressure of 50 mm Hg was achieved. Hypotensionwas maintained in the range of 40 to 50 mm Hg by further with-drawals or reinfusions of blood. After 45 minutes of sustainedhypotension, the animals were resuscitated using 1 of 2 randomlyassigned regimens. The sham group underwent all experimentalpreparations but was not subjected to hemorrhage or resuscitation.

All 3 experimental groups underwent exteriorization of thecremaster muscle for intravital microscopy. Video recordings ofeach animal’s microvasculature were captured before, during, andafter resuscitation to quantify endothelial cell–polymorphonuclear

neutrophil interactions. Polymorphonuclear neutrophil rolling,rolling velocity, and PMN adherence were measured at 15-minuteintervals for a total of 90 minutes. After completion of video re-cordings, vascular permeability was measured with an injection offluorescent-labeled bovine serum albumin. Vascular leakage wascalculated after 15 minutes by comparing the intensity of fluores-cence of the perivascular space with the vascular space. Postmor-tem, the cremaster muscle was analyzed immunohistochemicallyfor the expression of ICAM-1, an endothelial cell receptor thatstrongly interacts with PMN integrins. A single investigator gradedthe intensity of expression of ICAM-1 semiquantitatively.

Results:

1. There were no differences between groups in flow mechanics.2. Hypertonic saline-resuscitated animals displayed roughly

half the number of rolling PMNs and roughly one-fourththe amount of total PMN adherence when compared withthe RL group.

3. There were no significant differences between the HTS andsham groups.

4. The PMN rolling velocity tended to be greater in both HTSand sham groups compared with RL at all time points afterresuscitation.

5. The HTS group displayed 45% less vascular leakage thanthe RL group.

6. Vascular leakage was slightly higher in HTS than in shammice.

7. Cremasteric muscle vascular EC expression of ICAM-1 wassimilar in both HTS and RL animals.

8. Both circulating leukocyte and PMN counts tended to behigher in the HTS group than in both the sham and RL groups.

9. The proportion of circulating leukocytes that were PMNswas similar in all groups.

Current Surgery presents a comprehensive review of recent surgical and medical literature for the surgeon who wantsto stay well informed in the least amount of time. Our international board of editors selects significant articles to reviewand provides commentary. The editorial board welcomes suggestions of topics or specific articles from our readers.

CURRENT SURGERY • © 2004 by the Association of Program Directors in Surgery 0149-7944/04/$30.00Published by Elsevier Inc.

247

Conclusions: When compared with resuscitation with ring-er’s lactate, hypertonic saline resulted in decreased adherence ofPMNs to endothelium. Lactated ringer-resuscitated animalsdisplayed an early and sustained elevation in vascular leakage in

vivo that was not observed in HTS-resuscitated animals. Theauthors suggest that these findings support an immunomodu-latory role for hypertonic saline in the management of hemor-rhagic shock.

REVIEWER COMMENTS

This article addresses directly, in an elegant and well-definedhemorrhagic shock model, the effects of HTS on EC-PMNinteractions. The study provides novel evidence that HTS spe-cifically decreases the number of rolling and adherent PMNswhile increasing PMN rolling velocities. Other studies haveemployed HTS-sugar solutions and fluorescent labeling ofPMNs, both of which have an antiadhesive influence on PMNs.The current study uses an HTS solution free of sugar, and theresults suggest that the hypertonicity of the resuscitation fluidalso impacts neutrophil adhesive properties.

This study examines in vivo postcapillary venous permeabil-ity after resuscitation after hemorrhagic shock. When HTS wasused in place of RL, there was almost half the amount of vas-cular leakage. Despite a strong association between HTS-medi-ated decreases in EC-PMN interactions and vascular leakage, adirect causal relationship was not found.

Although other studies have provided evidence supporting

HTS-mediated modulation of PMN and EC adhesion mole-cule expression, including ICAM-1, this study failed to show asignificant difference in ICAM-1 expression between thedifferent experimental groups. The authors reason that thisresult may indicate that ICAM-1 may not be the principaltarget of HTS-mediated effects, or that this model did notprovide a strong enough activating stimulus. They suggest thatICAM-1 knockout models may provide a more direct means ofestablishing the effects of HTS on ICAM-1 and other adhesionmolecules.

In summary, these authors suggest that use of HTS results indecreased vascular permeability that may be mediated by analteration of EC-PMN interactions. Their data does not reflecta role for ICAM-1 as a source for the observed decrease inneutrophil adherence to endothelial cells. These findings pro-vide experimental evidence for use of HTS instead of RL in theresuscitation of hemorrhagic shock.

ACUTE HAEMODYNAMIC EFFECTS OF AHYPERTONIC SALINE/DEXTRAN SOLUTION INSTABLE PATIENTS WITH SEVERE SEPSIS.Oliveira RP, Weingartner R, Ribas EO, Moraes RS,Friedman G. Intensive Care Med. 2002;28:1574-1581.

Objective: To study the hemodynamic effects of a hyper-tonic saline/dextran solution compared with a normal salinesolution in patients with severe sepsis.

Design: Prospective, double-blind, randomized control study.

Setting: Central Intensive Care Unit, Irmandade da SantaCasa de Misericordia, Porto Alegre, Brazil.

Participants: Twenty-nine patients with sepsis and pulmo-nary artery occlusive pressures less than 12 mm Hg.

Methods: Patients were randomized to receive 250 cc ofblinded solutions of either normal saline or hypertonic saline/dextran. Hemodynamic measurements, blood gas analysis, and

serum sodium levels were measured at 30 minutes, 60 minutes,120 minutes, and 180 minutes.

Results:

1. Pulmonary artery wedge pressures were higher in the hypertonicsaline/dextran (HSS) group at 30 minutes and 60 minutes.

2. Cardiac index was also significantly higher in the HSSgroup at 30 minutes, 60 minutes, and 120 minutes.

3. In a similar manner the HSS group had higher stroke vol-ume indexes at 30 minutes and 60 minutes.

4. Systemic vascular resistance was found to be lower in theHSS-treated group.

5. Serum sodium levels in the hypertonic saline/dextran groupwere predictably higher than those of the normal salinegroup; yet, they still remained within normal range.

Conclusions: Hypertonic saline/dextran when comparedwith normal saline may improve cardiovascular performance insepsis with less of a volume load than seen after resuscitationwith isotonic fluids.

REVIEWER COMMENTS

This study examined the hemodynamic effects of hypertonicsaline/dextran resuscitation in comparison with normal salineresuscitation in septic patients. Their findings support the premisethat hypertonic resuscitation improves cardiac output and oxygendelivery in this population. Unfortunately, the lack of comparabil-

ity between study groups prohibits interpretation of the clinicalrelevance of improved hemodynamic performance.

One would expect a truly septic patient to have a low systemicvascular resistance. It is curious that the “septic population” studiedhad high systemic vascular resistances. It is not clear whether this

248 CURRENT SURGERY • Volume 61/Number 3 • May/June 2004

was the byproduct of pressor therapy or the baseline measurementof the study participants. If the latter is true, the findings mayreflect a less critically ill population than that often seen in the faceof florid septic shock. The fact that VO2 did not change supportsthe commonly seen phenomenon of decreased oxygen extraction

(despite degree of O2 delivery) during sepsis. This study docu-ments one possible benefit of hypertonic saline resuscitation in thesetting of septic shock. The role that adequate perfusion plays as adeterrent to persistent inflammatory response, and the progressiontoward multisystem organ failure is a topic of ongoing research.

METABOLIC AND HEMODYNAMIC EFFECTS OFHYPERTONIC SALINE SOLUTIONS: SODIUM-LACTATE VERSUS SODIUM CHLORIDE INFUSION INPOSTOPERATIVE PATIENTS.Mustafa I, Leverve X, Shock. 2002;18:306-310.

Objective: To compare the metabolic and cardiovascular ef-fects of postoperative resuscitation with hypertonic sodium lac-tate and hypertonic sodium chloride.

Design: Prospective, controlled clinical trial.

Setting: Intensive Care Unit, Harapan Kita National Cardio-vascular Center, Jakarta, Indonesia.

Participants: Sixty patients who underwent coronary arterybypass grafting (CABG) and were divided into 3 groups.

1. Coronary artery bypass grafting on cardiopulmonary by-pass (CPB) who received postoperative hypertonic sodiumlactate [20 patients].

2. Coronary artery bypass grafting off-pump who received hy-pertonic sodium lactate [20 patients].

3. Coronary artery bypass grafting on cardiopulmonary by-pass who received postoperative hypertonic sodium chlo-ride [20 patients].

Methods: Fourteen to 16 hours after surgery, patients in eachgroup received 2.5-cc/kg hypertonic solution for 15 minutes viaa central line. Hemodynamic parameters (heart rate, systolic,diastolic, mean arterial pressure, cardiac output) and blood gasanalysis (arterial and mixed venous) were recorded before infu-sion (T15 min), at the end of infusion (T0), and 2 hours aftercompletion of infusion (T120). The following parameters weremeasured at each time point:

1. Heart rate2. Systolic, diastolic, and mean arterial pressure3. Cardiac index, oxygen delivery, oxygen consumption (cal-

culated from Fick’s equation), and oxygen extraction4. PaO2, PaCO2, arterial pH, bicarbonate, glucose, lactate and

sodium

Results:

1. Blood lactate was not affected in the hypertonic sodium chlo-ride group (CPB-NaCl), whereas it rose significantly in thehypertonic sodium lactate groups. The off-pump hypertonicsodium lactate group (OPCPB-Lac) had an earlier resolutionto lactemia than the on-pump group (CPB-Lac); this suggestslactate was metabolized in both groups, although more slowlyin those patients who had been on cardiopulmonary bypass.

2. Plasma sodium levels rose 3% to 4% in all 3 groups afterinfusion.

3. Cardiac index increased 21%, 29%, and 32% in CPB-NaCl, CPB-Lac, and OPCAB-Lac groups, respectively.

4. Oxygen delivery also increased in all 3 groups, whereas asignificant increase in oxygen consumption was seen only inthe CPB-NaCl and OPCAB-Lac groups but not in theCPB-Lac group.

5. Net oxygenation as measured by the oxygen extraction fractionwas decreased significantly in both hypertonic lactate groupsbut not significantly different in the CPB-NaCl group.

6. Hypertonic lactate infusion groups had a postinterventionpH increase of 0.04 to 0.05, whereas the hypertonic salinegroup had a postintervention pH decrease of 0.02 units. Thesechanges in pH were paralled with increased serum bicar-bonate in the hypertonic lactate groups and decreased se-rum bicarbonate in the hypertonic saline group.

Conclusions: Hypertonic lactate and hypertonic salineincrease cardiac index and oxygen delivery in patients whohave undergone placement of coronary artery bypass grafts.The anionic nature of the resuscitation fluid affected serumpH postinfusion. An increase in serum pH was seen afterinfusion of hypertonic lactate, whereas a decrease in serumpH was noted in patients who received hypertonic saline.Predictively, the oxygen extraction ratio was slightly lower inthe more alkalotic patients resuscitated with hypertonic so-dium lactate. Although lactate levels in these groups roseafter infusion, evidence of lactate metabolism is seen as earlyas 2 hours after intervention. Sodium levels all predictivelyincreased, as did serum glucose levels. The biophysiology ofthis inducible hyperglycemia is unclear. Gluconeogenesis orinduction of glycogen breakdown could play a role in thisphenomenon.

REVIEWER COMMENTS

This study compares the physiologic and metabolic effects ofhypertonic sodium chloride and hypertonic sodium lactate. Asseen in other studies, resuscitation with both hypertonic solu-

tions increased cardiac index and oxygen delivery. Previous ex-periments in the literature have focused on hypertonic sodiumchloride either with or without dextran. The authors of this article

CURRENT SURGERY • Volume 61/Number 3 • May/June 2004 249

attempt to discern whether using hypertonic sodium lactate caneliminate the effects of the chloride load inherent to hypertonicsaline with similar cardiovascular and oxygen delivery benefits.

Of interest, differences in pH and lactate were seen betweengroups. These differences can be attributed to the major role thatsodium ions and chloride anions play in determination of the“strong ion difference” (SID). This ion difference is one of themajor contributors to acid/base balance in serum. Although oxy-gen delivery was enhanced, the oxygen extraction ratio was less forthe more alkalotic, lactate-resuscitated groups. Oxygen-hemoglobindissociation principles support this finding of less oxygen extraction in

an alkaline environment. Thus, the overall physiologic effect ofimproved oxygen delivery is determined by how much substrate isactually extracted for aerobic metabolism on the cellular level.

Although differences in study parameters were seen, thereappeared to be no untoward clinical implications to the use ofhypertonic resuscitation fluids in these stable postoperative pa-tients. Elsewhere in the literature, the use of hypertonic fluidshas focused on the more acute setting of hemorrhagic or septicshock. The use of hypertonic sodium lactate as an alternative tohypertonic saline or isotonic fluids in these more acute settingswill require further investigation.

REVIEWER SUMMARY

Patients often require resuscitation after hemorrhage or becausethey are severely vasodilated from sepsis. In the acute setting, thebody orchestrates a complex play of compensatory events, whichcan aid in survival or initiate a spiral toward multisystem failure.Much of our early experience during wartime resuscitation in-volved use of inexpensive and available isotonic crystalloid volumereplacements. Investigators have examined crystalloid and colloidformulas in search of a fluid that would adequately restore circu-lating volume, yet not exacerbate the inflammatory response andpersistent microvascular leak often seen after severe shock.

In the 1980s, hypertonic saline (HTS) was introduced as apossible alternative to isotonic crystalloids and colloids. In earlyinvestigations, resuscitation with HTS yielded an increase incardiac output and mean arterial pressures. In the articles pre-sented here, Oliveira et al and Mustafa and Leverve also ob-served improved hemodynamic parameters after HTS infusion.Although these effects are most likely the result of volume ex-pansion, animal studies show that coronary blood flow is en-hanced when HTS is used for resuscitation. Increased perfusionof the myocardium adds not only to cardiac endurance but alsohas an inotropic effect during the critical period of resuscitation.1

As one might expect, the cardiac benefits of hypertonic re-suscitation are accompanied by improved perfusion to othercritical vascular beds. Splanchnic and renal perfusion increase inanimals resuscitated with HTS after hemorrhage or inducedsepsis.2 Improved splanchnic perfusion has been linked to de-creased bacterial translocation in some of these models.3

As our understanding of systemic inflammatory responsesyndrome (SIRS) increases, so does our desire to tame rampantmediators with immune-modulation. Pascual et al have shownthat hypertonic saline decreases PMN-endothelium interac-tions and microvascular leak. These findings offer a glimpseinto the complex molecular puzzle depicting the evolution ofSIRS. In the literature, there are other pieces to this puzzle, suchas characterization adhesion molecules, cytokine activity, andexpression after HTS resuscitation.4,5 As the molecular physi-ology of the immune response is further defined, it will offerinsights into the benefits and risks of hypertonic, isotonic, andcolloid resuscitation fluids.

Why is hypertonic saline not the accepted fluid of choice after

acute hemorrhage and sepsis? Even with all of the documentedbenefits, there have been concerns as to the metabolic implicationsof infusing hypertonic fluids in volumes needed for resuscitation.As seen in the study by Mustafa et al, the “chloride load” of hyper-tonic saline can decrease the strong ion difference, which contrib-utes to acidosis. Other authors have shown that HTS not only“worsens” acidosis but also increases serum osmolality. Mustafa etal suggests that use of hypertonic sodium lactate may offer analkalotic alternative to HTS, for resuscitation. It is difficult to ex-trapolate the physiologic implications of hypertonic lactate load inpatients with normal hepatic function post-CABG to patients inflorid shock, who may have altered hepatic function. Alternatively,other investigators have raised concerns over the metabolic effect ofhypertonic saline in patients with preexisting acidosis from shock.Earlier studies added dextran to HTS in an attempt to maintain theosmotic effect of the fluid but to blunt the metabolic effect of aconcentrated electrolyte load. Some of the complications seen inthese earlier investigations were directly related to the artificial col-loid (dextran) and included anaphylaxis, impaired renal clearance,and impaired hemostasis. Significant bleeding after HTS-dextranhas been noted in models of “uncontrolled” hemorrhage, a groupwith universally worse prognosis overall. These complications, al-though seen in animal studies, are rare in humans; clinical use hasproven HTS and HTS-dextran to be safe resuscitative fluids.6

Concerns of the metabolic implications of hypertonic fluidsare still raised in the literature. “How harmful is the resultantacidosis?” Recent research in lung protective strategies arguethat relative acidosis is tolerated and may even be beneficial.(Remember oxygen-hemoglobin dissociation mechanics?)How harmful is relative hyperosmolality? The experience withthe use of mannitol after traumatic brain injury suggests thatserum osmoles as high as 310 mOsm/kg can be tolerated withacceptable outcomes. As the use of HTS in the treatment ofhead injury gains acceptance, we will have new reference pointsfor safe ranges outside of what we currently define as “normal”physiologic parameters. The studies presented here suggestthere may be hemodynamic, immunomodulatory, and meta-bolic reasons to use hypertonic saline as the resuscitation fluidof choice after hemorrhage or in early septic shock.

doi: 10.1016/j.cursur.2003.11.002

250 CURRENT SURGERY • Volume 61/Number 3 • May/June 2004

REFERENCES1. Miller R. Anesthesia. Philadelphia, PA: Churchill Living-

ston; 2000:2383-2399.

2. Oi Y, Anders A, Mats S, Ewert S, Mats D, Haljamae H.Hypertonic saline-dextran improves intestinal perfusionand survival in porcine endotoxin shock. Crit Care Med.2000;28:2843-2850.

3. Hirsh M, Dyogovskaya L, Yulia B, Krausz M. Reducedrate of bacterial translocation and improved variables ofnatural killer cell and T-cell activity in rats surviving con-trolled hemorrhagic shock and treated with hypertonicsaline. Crit Care Med. 2002;30:861-867.

4. Angle N, Cabello-Passini R, Hoyt D, et al. Hypertonicsaline infusion: can it regulate human neutrophil func-tion? Shock. 2000;14:503-508.

5. Rhee P, Wang D, Ruff P, et al. Human neutrophil acti-vation and increased adhesion by various resuscitation flu-ids. Crit Care Med. 2000;28(1):74-78.

6. Orlinsky M, Shoemaker W, Reis E, Kerstein M. Currentcontroversies in shock and resuscitation. Surg Clin N Am.2001;81:1217-1262.

QUESTIONS AND ANSWERS

Questions

1. A rise in serum pH causes

a. hyperventilationb. decreased oxygen-hemoglobin dissociationc. hyperglycemiad. seizurese. decreased SvO2

2. A decrease in the strong ion difference results in

a. hypoglycemiab. lactic acidosisc. acidemiad. hypochloremic metabolic alkalosise. hypoventilation

3. Hypertonic saline when used for resuscitation after hemor-rhage

a. causes an increase in serum pHb. increases microvascular leakc. decreases PMN adherence to endothelial cellsd. worsens pulmonary edemae. increases oxygen requirements

4. Hypertonic resuscitation fluids

a. cause hypoglygemiab. increase cardiac indexc. must be given in a 3:1 ratio to volume of blood lossd. increase interstitial oncotic pressuree. increase PMN adhesion to microvascular endothelium

5. Dextran is added to hypertonic saline in resuscitation trials

a. to add nutrition to the formulab. to buffer pHc. to treat coagulopathyd. to maintain oncotic pressure while lessening the effect

of increased NaCl loade. to offset the cost of the hypertonic formula

Answers

1. b2. c3. c4. b5. d

Breast

Is There a Place for Aggressive Surgery in Stage IV BreastCancer?Guest Reviewer: John A. Singer, MD, St. Agnes HealthCare, Baltimore, Maryland

DOES AGGRESSIVE LOCAL THERAPY IMPROVESURVIVAL IN METASTATIC BREAST CANCER?Khan SA, Stewart AK, Morrow M. Surgery. 2002;132:620-627.

Objective: To evaluate whether the local treatment of breastcancer alters survival in women who have metastatic disease atthe time of initial therapy.

Design: A retrospective analysis.

Setting: Data gathered by the National Cancer Data Base(NCDB) of the American College of Surgeons’ Commission onCancer.

Participants: Patients with primary breast cancer diagnosedbetween 1990 and 1993 and with clinical or pathologic StageIV disease at the time of diagnosis.

CURRENT SURGERY • Volume 61/Number 3 • May/June 2004 251