Tag Archives: fluid

FIRST: Fluids in Resuscitation of Severe Trauma

This is the first randomized, controlled, double-blind study comparing crystalloids with isotonic colloids in trauma. 0.9% saline was compared with hydroxyethyl starch, HES 130/0.4, as a resuscitation fluid in pre-defined subgroups of penetrating and blunt trauma. While a primary outcome measure of gastrointestinal recovery might not seem an obvious choice to some of us, previous research has indicated this to be an issue with crystalloid and the authors clearly defined this as a predefined outcome when registering the trial here.

I don't have any pictures of colloids. Here's where I work.

Colloids tend to require smaller volumes than crystalloid to achieve the same degree of plasma expansion. An interesting finding in this study is that the volume of saline administered was 1.5 times that of hydroxyethyl starch – a very similar ratio to that seen in the SAFE study which compared saline with 4% albumin in intensive care patients.
The authors assert: “..the better lactate clearance in the P-HES group indicated superior tissue resuscitation with the colloid.” There are a number of reasons why this might be a bit of stretch, including the use of epinephrine in some patients which is known to be a cause of hyperlactataemia.
This is a small study whose conclusions should be treated with caution, but which provides an important contribution to the pool of fluid resuscitation literature. If you have full text access to the British Journal of Anaesthesia, the letters pages provide excellent critiques and responses regarding potential flaws in this paper. Nevertheless, it’s one to know about – I’m sure the FIRST trial is going to be quoted for some time to come, including, I suspect, by the manufacturers of certain colloids.

Background The role of fluids in trauma resuscitation is controversial. We compared resuscitation with 0.9% saline vs hydroxyethyl starch, HES 130/0.4, in severe trauma with respect to resuscitation, fluid volume, gastrointestinal recovery, renal function, and blood product requirements.

Methods Randomized, controlled, double-blind study of severely injured patients requiring>3 litres of fluid resuscitation. Blunt and penetrating trauma were randomized separately. Patients were followed up for 30 days.

Results A total of 115 patients were randomized; of which, 109 were studied. For patients with penetrating trauma (n=67), the mean (sd) fluid requirements were 5.1 (2.7) litres in the HES group and 7.4 (4.3) litres in the saline group (P<0.001). In blunt trauma (n=42), there was no difference in study fluid requirements, but the HES group required significantly more blood products [packed red blood cell volumes 2943 (1628) vs 1473 (1071) ml, P=0.005] and was more severely injured than the saline group (median injury severity score 29.5 vs 18; P=0.01). Haemodynamic data were similar, but, in the penetrating group, plasma lactate concentrations were lower over the first 4 h (P=0.029) and on day 1 with HES than with saline [2.1 (1.4) vs 3.2 (2.2) mmol litre−1; P=0.017]. There was no difference between any groups in time to recovery of bowel function or mortality. In penetrating trauma, renal injury occurred more frequently in the saline group than the HES group (16% vs 0%; P=0.018). In penetrating trauma, maximum sequential organ function scores were lower with HES than with saline (median 2.4 vs 4.5, P=0.012). No differences were seen in safety measures in the blunt trauma patients.
Conclusions In penetrating trauma, HES provided significantly better lactate clearance and less renal injury than saline. No firm conclusions could be drawn for blunt trauma.

Resuscitation with hydroxyethyl starch improves renal function and lactate clearance in penetrating trauma in a randomized controlled study: the FIRST trial (Fluids in Resuscitation of Severe Trauma)

Br J Anaesth. 2011 Nov;107(5):693-702

Prehospital fluids for head injury – keep it simple

Just in case you thought you might be missing some recent gem on what we should be giving patients with traumatic brain injury in the field: a team from Melbourne has reviewed the literature and concluded isotonic crystalloids (Ringer’s or Saline) are as good as anything else.

The early management of patients who have sustained traumatic brain injury is aimed at preventing secondary brain injury through avoidance of cerebral hypoxia and hypoperfusion. Especially in hypotensive patients, it has been postulated that hypertonic crystalloids and colloids might support mean arterial pressure more effectively by expanding intravascular volume without causing problematic cerebral oedema. We conducted a systematic review to investigate if hypertonic saline or colloids result in better outcomes than isotonic crystalloid solutions, as well as to determine the safety of minimal volume resuscitation, or delayed versus immediate fluid resuscitation during prehospital care for patients with traumatic brain injury. We identified nine randomized controlled trials and one cohort study examined the effects of hypertonic solutions (with or without colloid added) for prehospital fluid resuscitation. None has reported better survival and functional outcomes over the use of isotonic crystalloids. The only trial of restrictive resuscitation strategies was underpowered to demonstrate its safety compared with aggressive early fluid resuscitation in head injured patients, and maintenance of cerebral perfusion remains the top priority.

Review article: Prehospital fluid management in traumatic brain injury
Emerg Med Australas. 2011 Dec;23(6):665-76

Fluids contribute to acid-base disturbance on ICU

Image from Wikipedia
I enjoyed a paper from Critical Care Medicine this month which relates to a major bugbear of mine: the prescription of 0.9% saline for critically ill patients and the consequent metabolic acidosis this causes. However it did produce some interesting findings that helped me review my own biases here.
In short, an ICU team decided to reduce and where possible eliminate the use of high chloride fluids including 0.9% saline and Gelofusine and replace with lower chloride fluids, mainly Ringer’s Lactate (Hartmann’s solution).
It is known that saline causes a metabolic acidosis by elevating chloride and reducing the strong ion difference. This results in a normal anion gap, hyperchloraemic acidosis. The clinical significance of this is uncertain, but the iatrogenic acidosis is often confused by clinicians as a sign of severe illness, especially those clinicians that don’t look at the chloride or anion gap.
Not surprisingly, changing the fluid policy resulted in less acidosis (and also less hypernatraemia). There was however an increase in severe alkalaemia. The study was not designed to look at patient oriented outcomes.
My observations are:

  • This is an important reminder that saline causes acidosis
  • Because of the possibility of worsening alkalosis, fluid therapy choice should be individualised for an ICU patient based on their known acid-base issues; in some cases, saline may be appropriate.
  • These patients were managed for several days on an ICU. Alkalaemia is common on the ICU for reasons that include hypoalbuminaemia, furosemide use, and iatrogenic hyperventilation. These factors are less relevant in the ED resuscitation population where such a degree of alkalaemia is rarely seen.
  • The authors point out that their results are “consistent with previous acute treatment studies, which were conducted in the perioperative or experimental setting” – isn’t it a shame that ED-based studies are not forthcoming?

The authors point to an additional finding:

Furthermore, our results suggest that routine use of lactate fluids such as Hartmann’s or Ringer’s lactate is associated with a detectable iatrogenic increase in lactate in the first 48 hrs after ICU admission, when, presumably, lactate clearance is less effective.

While this is interesting, the mean [SD] lactate values in the two groups were 1.79 [1.57] and 2.05 [1.61] so while statistically significant I suspect this is clinically irrelevant. And as we know, the cause of a raised lactate is more of a concern than the fact of a raised lactate
A significant benefit of the change in fluid policy was a signficant cost saving, largely due to the omission of Gelofusine.
For me, this study reassures me that my current practice of preferring Ringer’s Lactate to Saline in the resuscitation setting is likely to minimise iatrogenic acidosis without significantly elevating the lactate, in a population rarely afflicted by significant alkalaemia.
The biochemical effects of restricting chloride-rich fluids in intensive care
Crit Care Med. 2011 Nov;39(11):2419-2424
[EXPAND Abstract]

Objective: To determine the biochemical effects of restricting the use of chloride-rich intravenous fluids in critically ill patients.

Design: Prospective, open-label, before-and-after study.

Setting: University-affiliated intensive care unit.

Patients: A cohort of 828 consecutive patients admitted over 6 months from February 2008 and cohort of 816 consecutive patients admitted over 6 months from February 2009.

Interventions: We collected biochemical and fluid use data during standard practice without clinician awareness. After a 6-month period of education and preparation, we restricted the use of chloride-rich fluids (0.9% saline [Baxter, Sydney, Australia], Gelofusine [BBraun, Melsungen, Germany], and Albumex 4 [CSL Bioplasma, Melbourne, Australia]) in the intensive care unit and made them available only on specific intensive care unit specialist prescription.

Measurements and Main Results: Saline prescription decreased from 2411 L in the control group to 52 L in the intervention group (p < .001), Gelofusine from 538 to 0 L (p < .001), and Albumex 4 from 269 to 80 L (p < .001). As expected, Hartmann’s lactated solution prescription increased from 469 to 3205 L (p < .001), Plasma-Lyte from 65 to 160 L (p < .05), and chloride-poor Albumex 20 from 87 to 268 L (p < .001). After intervention, the incidence of severe metabolic acidosis (standard base excess5 mEq/L) and alkalemia (pH >7.5) with an increase from 25.4% to 32.8% and 10.5% to 14.7%, respectively (p < .001). The time-weighted mean chloride level decreased from 104.9 ± 4.9 to 102.5 ± 4.6 mmol/L (p < .001), whereas the time-weighted mean standard base excess increased from 0.5 ± 4.5 to 1.8 ± 4.7 mmol/L (p < .001), mean bicarbonate from 25.3 ± 4.0 to 26.4 ± 4.1 mmol/L (p < .001) and mean pH from 7.40 ± 0.06 to 7.42 ± 0.06 (p < .001). Overall fluid costs decreased from $15,077 (U.S.) to $3,915.

Conclusions: In a tertiary intensive care unit in Australia, restricting the use of chloride-rich fluids significantly affected electrolyte and acid-base status. The choice of fluids significantly modulates acid-base status in critically ill patients.


Pre-hospital hypertonic saline during ACLS

A newly published study examines pre-hospital hypertonic saline during CPR. A randomised trial compared 7.2% hypertonic saline / hydroxyethyl starch with hydroxyethyl starch alone in over 200 adult patients with non-traumatic out-of-hospital cardiac arrest. The volume infused was 2 ml /kg over 10 mins. All patients were resuscitated by the physicians of the Emergency Medical System (EMS) in Bonn, Germany.
There were no differences in survival to admission or discharge. There was a barely statistically significant increase in those survivors with higher cerebral performance categories (1 or 2) in the hypertonic saline group, inviting further study. The study was conducted from 2001 to 2004 (according to the 2000 CPR-Guidelines), so took an interestingly long time to see print.
Randomised study of hypertonic saline infusion during resuscitation from out-of-hospital cardiac arrest
Resuscitation. 2011 Sep 19. [Epub ahead of print]
[EXPAND Click to read abstract]

Aim of the study Animal models of hypertonic saline infusion during cardiopulmonary resuscitation (CPR) improve survival, as well as myocardial and cerebral perfusion during CPR. We studied the effect of hypertonic saline infusion during CPR (Guidelines 2000) on survival to hospital admission and hospital discharge, and neurological outcome on hospital discharge.

Methods The study was performed by the EMS of Bonn, Germany, with ethical committee approval. Study inclusion criteria were non-traumatic out-of-hospital cardiac arrest, aged 18–80 years, and given of adrenaline (epinephrine) during CPR. Patients were randomly infused 2 ml kg−1 HHS (7.2% NaCl with 6% hydroxyethyl starch 200,000/0.5 [HES]) or HES over 10 min.

Results 203 patients were randomised between May 2001 and June 2004. After HHS infusion, plasma sodium concentration increased significantly to 162 ± 36 mmol l−1 at 10 min after infusion and decreased to near normal (144 ± 6 mmol l−1) at hospital admission. Survival to hospital admission and hospital discharge was similar in both groups (50/100 HHS vs. 49/103 HES for hospital admission, 23/100 HHS vs. 22/103 HES for hospital discharge). There was a small improvement in neurological outcome in survivors on discharge (cerebral performance category 1 or 2) in the HHS group compared to the HES group (13/100 HHS vs. 5/100 HES, p < 0.05, odds-ratio 2.9, 95% confidence interval 1.004–8.5).
Conclusion Hypertonic saline infusion during CPR using Guidelines 2000 did not improve survival to hospital admission or hospital discharge. There was a small improvement with hypertonic saline in the secondary endpoint of neurological outcome on discharge in survivors. Further adequately powered studies using current guidelines are needed.


Easy rapid infusion set up

Kapoor and Singh's system from the Open Access article - click for explanation

Here’s a nice and simple set up for rapid iv infusions using simple cheap equipment

Full details at the Scandinavian Journal Site
Novel rapid infusion device for patients in emergency situations
Scand J Trauma Resusc Emerg Med. 2011 Jun 10;19:35 (Free Full Text)

Delta CVP with PEEP and fluid responsiveness

I’ve been (and remain) critical of the use of CVP to determine ‘filling status’ or more accurately volume-responsiveness, even using CVP trends; I’m generally in agreement with Dr Marik’s bold statement that “CVP should not be used to make clinical decisions regarding fluid management”1. However there might now appear to be a way of using CVP for this purpose.
Increasing PEEP in patients undergoing positive pressure ventilation can increase the CVP. It has been demonstrated in a small study of cardiac surgical patients2 that the degree to which a 10cmH2O increase in PEEP changes the CVP correlates with fluid responsiveness. The fluid responsiveness was determined by the change in cardiac output measured by thermodilution after a passive leg raise.
There are a number of limitations to this study that should prevent us from immediately extrapolating this method of determining fluid responsiveness to our ED / critical care patients, but the concept is interesting. This can be added to the growing pile of dynamic measures of circulatory filling.

Background Changes in central venous pressure (CVP) rather than absolute values may be used to guide fluid therapy in critically ill patients undergoing mechanical ventilation. We conducted a study comparing the changes in the CVP produced by an increase in PEEP and stroke volume variation (SVV) as indicators of fluid responsiveness. Fluid responsiveness was assessed by the changes in cardiac output (CO) produced by passive leg raising (PLR).

Methods In 20 fully mechanically ventilated patients after cardiac surgery, PEEP was increased +10 cm H2O for 5 min followed by PLR. CVP, SVV, and thermodilution CO were measured before, during, and directly after the PEEP challenge and 30° PLR. The CO increase >7% upon PLR was used to define responders.

Results Twenty patients were included; of whom, 10 responded to PLR. The increase in CO by PLR directly related (r=0.77, P<0.001) to the increase in CVP by PEEP. PLR responsiveness was predicted by the PEEP-induced increase in CVP [area under receiver-operating characteristic (AUROC) curve 0.99, P<0.001] and by baseline SVV (AUROC 0.90, P=0.003). The AUROC's for dCVP and SVV did not differ significantly (P=0.299).
Conclusions Our data in mechanically ventilated, cardiac surgery patients suggest that the newly defined parameter, PEEP-induced CVP changes, like SVV, appears to be a good parameter to predict fluid responsiveness.

1. Does central venous pressure predict fluid responsiveness? A systematic review of the literature and the tale of seven mares.
Chest. 2008 Jul;134(1):172-8
Full Text Link
2. Predicting cardiac output responses to passive leg raising by a PEEP-induced increase in central venous pressure, in cardiac surgery patients.
Br J Anaesth. 2011 Aug;107(2):251-7

Hypovolaemic shock and pre-hospital hypertonic saline

No benefit was shown in a trial of hypertonic saline (with or without dextran) versus 0.9% saline in patients with hemorrhagic shock, in a study that was terminated early. Compare this to a similar study on head injured patients without shock by the same investigators.

OBJECTIVE: To determine whether out-of-hospital administration of hypertonic fluids would improve survival after severe injury with hemorrhagic shock.
BACKGROUND: Hypertonic fluids have potential benefit in the resuscitation of severely injured patients because of rapid restoration of tissue perfusion, with a smaller volume, and modulation of the inflammatory response, to reduce subsequent organ injury.
METHODS: Multicenter, randomized, blinded clinical trial, May 2006 to August 2008, 114 emergency medical services agencies in North America within the Resuscitation Outcomes Consortium. Inclusion criteria: injured patients, age ≥ 15 years with hypovolemic shock (systolic blood pressure ≤ 70 mm Hg or systolic blood pressure 71-90 mm Hg with heart rate ≥ 108 beats per minute). Initial resuscitation fluid, 250 mL of either 7.5% saline per 6% dextran 70 (hypertonic saline/dextran, HSD), 7.5% saline (hypertonic saline, HS), or 0.9% saline (normal saline, NS) administered by out-of-hospital providers. Primary outcome was 28-day survival. On the recommendation of the data and safety monitoring board, the study was stopped early (23% of proposed sample size) for futility and potential safety concern.
RESULTS: A total of 853 treated patients were enrolled, among whom 62% were with blunt trauma, 38% with penetrating. There was no difference in 28-day survival-HSD: 74.5% (0.1; 95% confidence interval [CI], -7.5 to 7.8); HS: 73.0% (-1.4; 95% CI, -8.7-6.0); and NS: 74.4%, P = 0.91. There was a higher mortality for the postrandomization subgroup of patients who did not receive blood transfusions in the first 24 hours, who received hypertonic fluids compared to NS [28-day mortality-HSD: 10% (5.2; 95% CI, 0.4-10.1); HS: 12.2% (7.4; 95% CI, 2.5-12.2); and NS: 4.8%, P < 0.01].
CONCLUSION: Among injured patients with hypovolemic shock, initial resuscitation fluid treatment with either HS or HSD compared with NS, did not result in superior 28-day survival. However, interpretation of these findings is limited by the early stopping of the trial.

Out-of-hospital hypertonic resuscitation after traumatic hypovolemic shock: a randomized, placebo controlled trial
Ann Surg. 2011 Mar;253(3):431-41

Fluid Bolus in African Children with Severe Infection

Much discussion has already taken place in the blogosphere about the FEAST study of fluid resuscitation in septic children. Although a well conducted study, its external validity to Western populations is dubious, particularly in view of the proportion of malaria in the cohorts studied.

In the words of my emergency physician colleague Dr Fiona Rae from Wrexham, UK:

“Interesting. As they say, a completely different population in a resource limited setting so it doesn’t translate to UK practice. Majority of these children had malaria and if I read correctly 32% had Hb < 5g/dl. Also 20-40mls/kg is quite a lot of fluid these days as an initial bolus other than in the sort of severely shocked patients that they seemed to exclude. Their overall mortality also seems to be lower than expected for this population.

If you work in an environment without ITU and a high incidence of malaria then its a useful study. They are not the sort of children I see in my resus room with shock though.”
Nicely put Fi!
You can also read an analysis of this study on Dr G’s blog – where you can find other posts on critical care and emergency medicine.

The role of fluid resuscitation in the treatment of children with shock and life-threatening infections who live in resource-limited settings is not established.
We randomly assigned children with severe febrile illness and impaired perfusion to receive boluses of 20 to 40 ml of 5% albumin solution (albumin-bolus group) or 0.9% saline solution (saline-bolus group) per kilogram of body weight or no bolus (control group) at the time of admission to a hospital in Uganda, Kenya, or Tanzania (stratum A); children with severe hypotension were randomly assigned to one of the bolus groups only (stratum B). Children with malnutrition or gastroenteritis were excluded. The primary end point was 48-hour mortality; secondary end points included pulmonary edema, increased intracranial pressure, and mortality or neurologic sequelae at 4 weeks.
The data and safety monitoring committee recommended halting recruitment after 3141 of the projected 3600 children in stratum A were enrolled. Malaria status (57% overall) and clinical severity were similar across groups. The 48-hour mortality was 10.6% (111 of 1050 children), 10.5% (110 of 1047 children), and 7.3% (76 of 1044 children) in the albumin-bolus, saline-bolus, and control groups, respectively (relative risk for saline bolus vs. control, 1.44; 95% confidence interval [CI], 1.09 to 1.90; P=0.01; relative risk for albumin bolus vs. saline bolus, 1.01; 95% CI, 0.78 to 1.29; P=0.96; and relative risk for any bolus vs. control, 1.45; 95% CI, 1.13 to 1.86; P=0.003). The 4-week mortality was 12.2%, 12.0%, and 8.7% in the three groups, respectively (P=0.004 for the comparison of bolus with control). Neurologic sequelae occurred in 2.2%, 1.9%, and 2.0% of the children in the respective groups (P=0.92), and pulmonary edema or increased intracranial pressure occurred in 2.6%, 2.2%, and 1.7% (P=0.17), respectively. In stratum B, 69% of the children (9 of 13) in the albumin-bolus group and 56% (9 of 16) in the saline-bolus group died (P=0.45). The results were consistent across centers and across subgroups according to the severity of shock and status with respect to malaria, coma, sepsis, acidosis, and severe anemia.
Fluid boluses significantly increased 48-hour mortality in critically ill children with impaired perfusion in these resource-limited settings in Africa.

Mortality after Fluid Bolus in African Children with Severe Infection
NEJM May 26, 2011 Full text available

CHEST study to evaluate starch

No results to report here, just a heads up that the CHEST study is underway: a randomised controlled trial of 7000 patients comparing of 6% hydroxyethyl starch (130/0.4) with 0.9% sodium chloride for all fluid resuscitation needs whilst in the intensive care unit (ICU).  This is how the authors explain the rationale for the study:

Much of the evidence currently available to inform clinicians on the efficacy and safety of starch solutions for fluid resuscitation involves studies conducted using older, high molecular weight and high molar substitution starches. Meta-analyses of these studies suggest that when comparing starches to other fluids, the relative risk of mortality ranges from 1.00 (95% CI 0.80–1.25) to 1.35 (95% CI 0.94–1.95) and for kidney failure 1.50 (95% CI 1.20–1.87). There are insufficient data, however, on the newer low molecular weight, low molar substitution starches. To date, most published studies on these newer generation starches have been conducted in perioperative settings with small sample sizes and limited follow-up. They have been designed to examine surrogate outcomes and not important patient outcomes such as mortality or renal failure.

It is possible to overdo the starch

These are some of the same people who brought us the SAFE study on albumin and the NICE-SUGAR study on glycaemic control, so this will be one to watch. It is anticipated that recruitment will be completed by December 2011.

PURPOSE: The intravenous fluid 6% hydroxyethyl starch (130/0.4) (6% HES 130/0.4) is used widely for resuscitation but there is limited information on its efficacy and safety. A large-scale multi-centre randomised controlled trial (CHEST) in critically ill patients is currently underway comparing fluid resuscitation with 6% HES 130/0.4 to 0.9% sodium chloride on 90-day mortality and other clinically relevant outcomes including renal injury. This report describes the study protocol.
METHODS: CHEST will recruit 7,000 patients to concealed, random, parallel assignment of either 6% HES 130/0.4 or 0.9% sodium chloride for all fluid resuscitation needs whilst in the intensive care unit (ICU). The primary outcome will be all-cause mortality at 90 days post-randomisation. Secondary outcomes will include incident renal injury, other organ failures, ICU and hospital mortality, length of ICU stay, quality of life at 6 months, health economic analyses and in patients with traumatic brain injury, functional outcome. Subgroup analyses will be conducted in four predefined subgroups. All analyses will be conducted on an intention-to-treat basis.
RESULTS AND CONCLUSIONS: The study run-in phase has been completed and the main trial commenced in April 2010. CHEST should generate results that will inform and influence prescribing of this commonly used resuscitation fluid.

The Crystalloid versus Hydroxyethyl Starch Trial: protocol for a multi-centre randomised controlled trial of fluid resuscitation with 6% hydroxyethyl starch (130/0.4) compared to 0.9% sodium chloride (saline) in intensive care patients on mortality
Intensive Care Med. 2011 May;37(5):816-823

Norepinephrine increases preload

Noradrenaline (norepinephrine) may improve blood pressure in part through its venoconstriction effects, providing more venous return to the heart which increases cardiac output. A study of septic shock patients supports this.
An accompanying editorial by Drs Milzman and Napoli comments: “This study tells us something we probably already knew, that norepinephrine (NE) has the ability to provide venoconstriction, increase central venous pressure, provide a marginal increase in cardiac output, and improve the MAP in patients with septic shock. Importantly, it also demonstrates that Passive Leg Raise (PLR) continues to be a good predictor of preload responsiveness even in the presence of low doses of NE.”

OBJECTIVE: To assess the effects of norepinephrine on cardiac preload, cardiac index, and preload dependency during septic shock.
DESIGN: Prospective interventional study.
SETTING: Medical Intensive Care Unit.
PATIENTS: We included 25 septic shock patients (62 ± 13 yrs old, Simplified Acute Physiology Score II 53 ± 12, lactate 3.5 ± 2.1 mmol/L, all receiving norepinephrine at baseline at 0.24 [25%-75% interquartile range: 0.12-0.48] μg/kg/min) with a positive passive leg raising test (defined by an increase in cardiac index ≥10%) and a diastolic arterial pressure ≤40 mm Hg.
INTERVENTIONS: We performed a passive leg raising test (during 1 min) at baseline. Immediately after, we increased the dose of norepinephrine (to 0.48 [0.36-0.71] μg/kg/min) and, when the hemodynamic status was stabilized, we performed a second passive leg raising test (during 1 min). We finally infused 500 mL saline.
MEASUREMENTS AND MAIN RESULTS: Increasing the dose of norepinephrine significantly increased central venous pressure (+23% ± 12%), left ventricular end-diastolic area (+9% ± 6%), E mitral wave (+19% ± 23%), and global end-diastolic volume (+9% ± 6%). Simultaneously, cardiac index significantly increased by 11% ± 7%, suggesting that norepinephrine had recruited some cardiac preload reserve. The second passive leg raising test increased cardiac index to a lesser extent than the baseline test (13% ± 8% vs. + 19% ± 6%, p < .05), suggesting that norepinephrine had decreased the degree of preload dependency. Volume infusion significantly increased cardiac index by 26% ± 15%. However, cardiac index increased by <15% in four patients (fluid unresponsive patients) while the baseline passive leg raising test was positive in these patients. In three of these four patients, the second passive leg raising test was also negative, i.e., the second passive leg raising test (after norepinephrine increase) predicted fluid responsiveness with a sensitivity of 95 [76-99]% and a specificity of 100 [30-100]%.
CONCLUSIONS: In septic patients with a positive passive leg raising test at baseline suggesting the presence of preload dependency, norepinephrine increased cardiac preload and cardiac index and reduced the degree of preload dependency.

Norepinephrine increases cardiac preload and reduces preload dependency assessed by passive leg raising in septic shock patients
Crit Care Med 2011;39(4):689-94