Sepsis research – let’s get some answers

December 17, 2013 by  
Filed under Acute Med, All Updates, ICU, Resus

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There’s so much debate on which components of Early Goal Directed Therapy in sepsis really make a difference. The good news is that three randomised controlled trials in the UK, Australasia, and North America, aim to answer the question, and the study design from the outset has been a collaboration that will allow the results to be pooled.

ProMISe is taking place in the UK, ProCESS in the US, and ARISE in Australasia.

sepsistrialssm

The Australasian study (ARISE) and is nearing completion. If you can recruit patients then please do. Listen to a podcast on this fantastic study with lead investigator Dr Anthony Delaney.

Colloids again: still no benefit.

November 16, 2013 by  
Filed under Acute Med, All Updates, EMS, ICU, Resus, Trauma

fluidinheloiconIt’s nice to have big randomised trials to guide critical care practice. The age-old crystalloid/colloid debate (is that still going?) has fueled a multicentre and multinational study in 2857 patients with hypovolaemic shock on intensive care units. Patients were classified as having sepsis, trauma, or other causes of hypovolaemic shock.

In the crystalloids group, allowed treatments included isotonic or hypertonic saline and any buffered solutions. In the colloids group, gelatins, albumin from 4-25%, dextrans, and hydroxyethyl starches were permitted.

The primary outcome of 28 day mortality was no different between groups. The study had an open-label design and recruitment took place over nine years.

This finding – no clinical benefit from colloids in critically ill patients – is in keeping with other major ICU trials of colloid therapy: Saline versus Albumin Fluid Evaluation (SAFE), Efficacy of Volume Substitution and Insulin Therapy in Severe Sepsis (VISEP), Scandinavian Starch for Severe Sepsis/Septic Shock (6S), and the Crystalloid versus Hydroxyethyl Starch Trial (CHEST).

Effects of fluid resuscitation with colloids vs crystalloids on mortality in critically ill patients presenting with hypovolemic shock: the CRISTAL randomized trial
JAMA. 2013 Nov 6;310(17):1809-17


 

IMPORTANCE: Evidence supporting the choice of intravenous colloid vs crystalloid solutions for management of hypovolemic shock remains unclear.

OBJECTIVE: To test whether use of colloids compared with crystalloids for fluid resuscitation alters mortality in patients admitted to the intensive care unit (ICU) with hypovolemic shock.

DESIGN, SETTING, AND PARTICIPANTS: A multicenter, randomized clinical trial stratified by case mix (sepsis, trauma, or hypovolemic shock without sepsis or trauma). Therapy in the Colloids Versus Crystalloids for the Resuscitation of the Critically Ill (CRISTAL) trial was open label but outcome assessment was blinded to treatment assignment. Recruitment began in February 2003 and ended in August 2012 of 2857 sequential ICU patients treated at 57 ICUs in France, Belgium, North Africa, and Canada; follow-up ended in November 2012.

INTERVENTIONS: Colloids (n = 1414; gelatins, dextrans, hydroxyethyl starches, or 4% or 20% of albumin) or crystalloids (n = 1443; isotonic or hypertonic saline or Ringer lactate solution) for all fluid interventions other than fluid maintenance throughout the ICU stay.

MAIN OUTCOMES AND MEASURES: The primary outcome was death within 28 days. Secondary outcomes included 90-day mortality; and days alive and not receiving renal replacement therapy, mechanical ventilation, or vasopressor therapy.

RESULTS: Within 28 days, there were 359 deaths (25.4%) in colloids group vs 390 deaths (27.0%) in crystalloids group (relative risk [RR], 0.96 [95% CI, 0.88 to 1.04]; P = .26). Within 90 days, there were 434 deaths (30.7%) in colloids group vs 493 deaths (34.2%) in crystalloids group (RR, 0.92 [95% CI, 0.86 to 0.99]; P = .03). Renal replacement therapy was used in 156 (11.0%) in colloids group vs 181 (12.5%) in crystalloids group (RR, 0.93 [95% CI, 0.83 to 1.03]; P = .19). There were more days alive without mechanical ventilation in the colloids group vs the crystalloids group by 7 days (mean: 2.1 vs 1.8 days, respectively; mean difference, 0.30 [95% CI, 0.09 to 0.48] days; P = .01) and by 28 days (mean: 14.6 vs 13.5 days; mean difference, 1.10 [95% CI, 0.14 to 2.06] days; P = .01) and alive without vasopressor therapy by 7 days (mean: 5.0 vs 4.7 days; mean difference, 0.30 [95% CI, -0.03 to 0.50] days; P = .04) and by 28 days (mean: 16.2 vs 15.2 days; mean difference, 1.04 [95% CI, -0.04 to 2.10] days; P = .03).

CONCLUSIONS AND RELEVANCE: Among ICU patients with hypovolemia, the use of colloids vs crystalloids did not result in a significant difference in 28-day mortality. Although 90-day mortality was lower among patients receiving colloids, this finding should be considered exploratory and requires further study before reaching conclusions about efficacy.

Hyperchloraemia and mortality

November 10, 2013 by  
Filed under All Updates, EMS, ICU, Resus

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Here’s something to add to the pile of data cautioning us to think before we acidify patients with saline. A study in Anesthesia and Analgesia using propensity matching provides retrospective evidence that patients who developed hyperchloremia after noncardiac surgery had worse outcomes.

For more information on why saline isn’t ‘normal’ see: What’s with all the chloride? An assault on salt

Hyperchloremia after noncardiac surgery is independently associated with increased morbidity and mortality: a propensity-matched cohort study
Anesth Analg. 2013 Aug;117(2):412-21


BACKGROUND: The use of normal saline is associated with hyperchloremic metabolic acidosis. In this study, we sought to determine the incidence of acute postoperative hyperchloremia (serum chloride >110 mEq/L) and whether this electrolyte disturbance is associated with an increase in length of hospital stay, morbidity, or 30-day postoperative mortality.

METHODS: Data were retrospectively collected on consecutive adult patients (>18 years of age) who underwent inpatient, noncardiac, nontransplant surgery between January 1, 2003 and December 31, 2008. The impact of postoperative hyperchloremia on patient morbidity and length of hospital stay was examined using propensity-matched and logistic multivariable analysis.

RESULTS: The dataset consisted of 22,851 surgical patients with normal preoperative serum chloride concentration and renal function. Acute postoperative hyperchloremia (serum chloride >110 mmol/L) is quite common, with an incidence of 22%. Patients were propensity-matched based on their likelihood to develop acute postoperative hyperchloremia. Of the 4955 patients with hyperchloremia after surgery, 4266 (85%) patients were matched to patients who had normal serum chloride levels after surgery. These 2 groups were well balanced with respect to all variables collected. The hyperchloremic group was at increased risk of mortality at 30 days postoperatively (3.0% vs 1.9%; odds ratio = 1.58; 95% confidence interval, 1.25-1.98) (relative risk 1.6 or risk increase of 1.1%) and had a longer hospital stay (7.0 days [interquartile range 4.1-12.3] compared with 6.3 [interquartile range 4.0-11.3]) than patients with normal postoperative serum chloride levels. Patients with postoperative hyperchloremia were more likely to have postoperative renal dysfunction. Using all preoperative variables and measured outcome variables in a logistic regression analysis, hyperchloremia remained an independent predictor of 30-day mortality with an odds ratio of 2.05 (95% confidence interval, 1.62-2.59).

CONCLUSION: This retrospective cohort trial demonstrates an association between hyperchloremia and poor postoperative outcome. Additional studies are required to demonstrate a causal relationship between these variables.

Predicting volume responsiveness

May 8, 2013 by  
Filed under Acute Med, All Updates, ICU, Resus, Ultrasound

IVCiconOne of the current Holy Grails of ED critical care is to find a reliable measure of fluid responsiveness in those patients with impaired organ perfusion, such as those with severe sepsis. This would enable us to identify those patients whose cardiac output would be improved by fluid therapy, and avoid subjecting ‘non-responders’ to the risks associated with fluid overload. Thanks to the uptake of early goal-directed therapy in sepsis, under-resuscitation is now much less common in the ED. However a growing evidence base reveals the dangers of over-resuscitation. We have a responsibility to optimise fluid therapy as best we can with the equipment we have, according to the latest evidence.

Inferior Vena Cava Ultrasound
Some tests of fluid responsiveness rely on the effect of respiration-induced changes in pleural pressure on the circulation. Inferior vena cava (IVC) size and degree of inspiratory collapse correlate with central venous pressure (CVP), but CVP is not a reliable predictor of volume status or responsiveness. Skinny, collapsing IVCs detected on ultrasound suggest volume responsiveness, but the lack of this finding does not exclude fluid responsiveness. IVC size and measurement can be affected by patient position, probe position, and a variety of health states from athleticism to increased abdominal pressure.

Pulse Pressure Variation
Respiratory pulse pressure variation derived from an arterial line trace in mechanically ventilated patients who are adequately sedated and receiving large tidal volumes can predict fluid responsiveness too. Variability in tidal volume, the presence of spontaneous breathing activity in a ventilated patient, and cardiac dysrhythmia can all confound the usefulness of this method.

End expiratory occlusion
Another test in mechanically ventilated patients is the end expiratory occlusion test. A positive pressure inspiratory breath cyclically decreases the left cardiac preload. Occluding the circuit at end-expiration prevents this cyclic impediment in left cardiac preload and acts like a fluid challenge. A 15 second expiratory occlusion is performed and an increase in pulse pressure or (if you can measure it) cardiac index predicts fluid responsiveness with a high degree of accuracy. The patient must be able to tolerate the 15 second interruption to ventilation without initiating a spontaneous breath.

Passive Leg Raise
Passive leg raising (PLR) involves measuring cardiac output (or its surrogate, velocity-time integral, or VTI) before and after tilting the semirecumbent patient supine and raising the legs to 45 degrees. This ‘autotransfuses’ blood from the lower limbs to the core and acts as a reversible fluid challenge. An increase in VTI identifies fluid responders. It would be nice if a PLR-induced increase in blood pressure revealed the answer, but BP does not reliably inform us of changes in cardiac output.

All these tests have limitations. Pulse pressure variation fails in patients with low respiratory system compliance, such as is found in ARDS(1). End-expiratory occlusion and PLR work in low respiratory system compliance, but the former still requires mechanical ventilation, and the latter requires a means of estimating cardiac output or a surrogate – oesophageal Doppler, the velocity-time integral measured by transthoracic echocardiography, and femoral artery flow (measured by arterial Doppler) have all been used. Non-invasive cardiac output monitors that are not operator dependent exist, such as the NICOM(TM) bioreactance device. Bioreactance cardiac output measurement is based on an analysis of relative phase shifts of an oscillating current that occurs when this current traverses the thoracic cavity. Its advantages are that it is noninvasive, it does not require endotracheal intubation or an arterial line, and it provides a good estimate of stroke volume in patients with atrial fibrillation.

A recent study evaluating the combination of PLR with NICOM(TM) bioreactance monitoring revealed that another tool could indicate volume responsiveness: an increase in carotid blood flow after PLR, as measured by carotid Doppler flow imaging(2). A threshold increase in carotid Doppler flow imaging of 20% for predicting volume responsiveness had a sensitivity and specificity of 94% and 86%, respectively. This was studied in a heterogenous group of hemodynamically unstable patients, suggesting applicability to the kind of patients who present to the ED, although numbers were small so more validation is required.

End-tidal carbon dioxide
End-tidal carbon dioxide (ETCO2) levels depend on cardiac output. Increasing cardiac output with a fluid challenge or PLR increases ETCO2,as long as ventilatory and metabolic conditions remain stable. In a recent small study, a PLR-induced increase in ETCO2 ≥ 5 % predicted a fluid-induced increase in cardiac index ≥ 15 % with sensitivity of 71 % (95 % confidence interval: 48-89 %) and specificity of 100 (82-100) %(3). The maximal effects of PLR on CI and ETCO2 were observed within 1 min.

So what can I use?
In summary, differentiating fluid responders from non-responders in the ED remains a challenge. The method used depends on available equipment and expertise, and whether the patient is spontaneously breathing or mechanically ventilated. The NICOM(TM) shows great promise but until your department can afford one, ultrasound is the way to go; small collapsing IVCs suggest fluid responders. Learning to measure a VTI on transthoracic echo or carotid Doppler flow will help you assess the response to a PLR in spontaneously ventilating patients. If they’re mechanically ventilated, then looking for an ETCO2 rise after PLR could be a simpler alternative.

Fluid responsiveness assessment – options in the Emergency Department

Inferior Vena Cava Ultrasound
Helpful if skinny / large degree of respirophasic collapse – suggests fluid responsive – ventilated or spontaneous breathing

Passive Leg Raise
Good in ventilated or spontaneous breathing patients; need to measure cardiac output or a surrogate, such as VTI (echo), NICOM(TM), carotid Doppler flow, or ETCO2 (if ventilation and metabolic status constant)

Pulse Pressure Variation
Requires full mechanical ventilation; no good if low respiratory compliance / disturbed heart-lung interaction

End expiratory occlusion
Requires mechanical ventilation and patient tolerance of 15 seconds of apnoea. Acts like a passive leg raise so need a measure of cardiac output or surrogate

 
I look forward to more studies on these modalities, and to trying some of them in the resus room at every available opportunity.

 

1. Passive leg-raising and end-expiratory occlusion tests perform better than pulse pressure variation in patients with low respiratory system compliance
Crit Care Med. 2012 Jan;40(1):152-7


OBJECTIVES: We tested whether the poor ability of pulse pressure variation to predict fluid responsiveness in cases of acute respiratory distress syndrome was related to low lung compliance. We also tested whether the changes in cardiac index induced by passive leg-raising and by an end-expiratory occlusion test were better than pulse pressure variation at predicting fluid responsiveness in acute respiratory distress syndrome patients.

DESIGN: Prospective study.

SETTING: Medical intensive care unit.

PATIENTS: We included 54 patients with circulatory shock (63 ± 13 yrs; Simplified Acute Physiology Score II, 63 ± 24). Twenty-seven patients had acute respiratory distress syndrome (compliance of the respiratory system, 22 ± 3 mL/cm H2O). In nonacute respiratory distress syndrome patients, the compliance of the respiratory system was 45 ± 9 mL/cm H2O.

MEASUREMENTS AND MAIN RESULTS: We measured the response of cardiac index (transpulmonary thermodilution) to fluid administration (500 mL saline). Before fluid administration, we recorded pulse pressure variation and the changes in pulse contour analysis-derived cardiac index induced by passive leg-raising and end-expiratory occlusion. Fluid increased cardiac index ≥ 15% (44% ± 39%) in 30 “responders.” Pulse pressure variation was significantly correlated with compliance of the respiratory system (r = .58), but not with tidal volume. The higher the compliance of the respiratory system, the better the prediction of fluid responsiveness by pulse pressure variation. A compliance of the respiratory system of 30 mL/cm H2O was the best cut-off for discriminating patients regarding the ability of pulse pressure variation to predict fluid responsiveness. If compliance of the respiratory system was >30 mL/cm H2O, then the area under the receiver-operating characteristics curve for predicting fluid responsiveness was not different for pulse pressure variation and the passive leg-raising and end-expiratory occlusion tests (0.98 ± 0.03, 0.91 ± 0.06, and 0.97 ± 0.03, respectively). By contrast, if compliance of the respiratory system was ≤ 30 mL/cm H2O, then the area under the receiver-operating characteristics curve was significantly lower for pulse pressure variation than for the passive leg-raising and end-expiratory occlusion tests (0.69 ± 0.10, 0.94 ± 0.05, and 0.93 ± 0.05, respectively).

CONCLUSIONS: The ability of pulse pressure variation to predict fluid responsiveness was inversely related to compliance of the respiratory system. If compliance of the respiratory system was ≤ 30 mL/cm H2O, then pulse pressure variation became less accurate for predicting fluid responsiveness. However, the passive leg-raising and end-expiratory occlusion tests remained valuable in such cases.

2. The use of bioreactance and carotid doppler to determine volume responsiveness and blood flow redistribution following passive leg raising in hemodynamically unstable patients
Chest. 2013 Feb 1;143(2):364-70


BACKGROUND: The clinical assessment of intravascular volume status and volume responsiveness is one of the most difficult tasks in critical care medicine. Furthermore, accumulating evidence suggests that both inadequate and overzealous fluid resuscitation are associated with poor outcomes. The objective of this study was to determine the predictive value of passive leg raising (PLR)- induced changes in stroke volume index (SVI) as assessed by bioreactance in predicting volume responsiveness in a heterogenous group of patients in the ICU. A secondary end point was to evaluate the change in carotid Doppler fl ow following the PLR maneuver.

METHODS: During an 8-month period, we collected clinical, hemodynamic, and carotid Doppler data on hemodynamically unstable patients in the ICU who underwent a PLR maneuver as part of our resuscitation protocol. A patient whose SVI increased by . 10% following a fluid challenge was considered a fluid responder.

RESULTS: A complete data set was available for 34 patients. Twenty-two patients (65%) had severe sepsis/septic shock, whereas 21 (62%) required vasopressor support and 19 (56%) required mechanical ventilation. Eighteen patients (53%) were volume responders. The PLR maneuver had a sensitivity of 94% and a specificity of 100% for predicting volume responsiveness (one false negative result). In the 19 patients undergoing mechanical ventilation, the stroke volume variation was 18.0% 5.1% in the responders and 14.8% 3.4% in the nonresponders ( P 5 .15). Carotid blood fl ow increased by 79% 32% after the PLR in the responders compared with 0.1% 14% in the nonresponders ( P , .0001). There was a strong correlation between the percent change in SVI by PLR and the concomitant percent change in carotid blood fl ow ( r 5 0.59, P 5 .0003). Using a threshold increase in carotid Doppler fl ow imaging of 20% for predicting volume responsiveness, there were two false positive results and one false negative result, giving a sensitivity and specificity of 94% and 86%, respectively. We noted a significant increase in the diameter of the common carotid artery in the fluid responders.

CONCLUSIONS: Monitoring the hemodynamic response to a PLR maneuver using bioreactance provides an accurate method of assessing volume responsiveness in critically ill patients. In addition, the study suggests that changes in carotid blood fl ow following a PLR maneuver may be a useful adjunctive method for determining fluid responsiveness in hemodynamically unstable patients.

3. End-tidal carbon dioxide is better than arterial pressure for predicting volume responsiveness by the passive leg raising test
Intensive Care Med. 2013 Jan;39(1):93-100


PURPOSE: In stable ventilatory and metabolic conditions, changes in end-tidal carbon dioxide (EtCO(2)) might reflect changes in cardiac index (CI). We tested whether EtCO(2) detects changes in CI induced by volume expansion and whether changes in EtCO(2) during passive leg raising (PLR) predict fluid responsiveness. We compared EtCO(2) and arterial pulse pressure for this purpose.

METHODS: We included 65 patients [Simplified Acute Physiology Score (SAPS) II = 57 ± 19, 37 males, under mechanical ventilation without spontaneous breathing, 15 % with chronic obstructive pulmonary disease, baseline CI = 2.9 ± 1.1 L/min/m(2)] in whom a fluid challenge was decided due to circulatory failure and who were monitored by an expiratory-CO(2) sensor and a PiCCO2 device. In all patients, we measured arterial pressure, EtCO(2), and CI before and after a fluid challenge. In 40 patients, PLR was performed before fluid administration. The PLR-induced changes in arterial pressure, EtCO(2), and CI were recorded.

RESULTS: Considering the whole population, the fluid-induced changes in EtCO(2) and CI were correlated (r (2) = 0.45, p = 0.0001). Considering the 40 patients in whom PLR was performed, volume expansion increased CI ≥ 15 % in 21 “volume responders.” A PLR-induced increase in EtCO(2) ≥ 5 % predicted a fluid-induced increase in CI ≥ 15 % with sensitivity of 71 % (95 % confidence interval: 48-89 %) and specificity of 100 (82-100) %. The prediction ability of the PLR-induced changes in CI was not different. The area under the receiver-operating characteristic (ROC) curve for the PLR-induced changes in pulse pressure was not significantly different from 0.5.

CONCLUSION: The changes in EtCO(2) induced by a PLR test predicted fluid responsiveness with reliability, while the changes in arterial pulse pressure did not.

Alternative ‘universal’ plasma donor

February 19, 2013 by  
Filed under All Updates, EMS, ICU, Resus, Trauma

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The group usually considered the universal donor for fresh frozen plasma because it contains no anti-A or anti-B antibodies is Type AB. Due to its limited availability the trauma service of the Mayo Clinic in Minnesota has been issuing thawed group A plasma to its flight crews who retrieve major trauma casualties from rural centres. This is given with packed group O red cells to patients who meet their prehospital massive transfusion protocol criteria. Some patients will inevitably receive ABO-incompatible plasma (namely patients with Group B or AB blood) which could theoretically give rise to haemolytic transfusion reactions, in which donor antibodies bind host red cells, activate complement, and give rise to anaemia, disseminated intravascular coagulation, acute kidney injury, and death. However:

  • the transfusion of platelets containing ABO-incompatible plasma is common, with up to 2 units of incompatible plasma per apheresis platelet unit, whereas haemolytic reactions to platelets are rare (1 in 9,000 incompatible platelet transfusions);
  • all reports of haemolytic reactions are caused by products that contain Group O plasma and there has never been a documented case of haemolysis as a result of products containing Group A plasma

A retrospective review showed no increased rates of adverse events with Type A compared with AB or ABO-compatible plasma. Since only a small absolute number of patients received an ABO-incompatible plasma transfusion, it could be argued that the study is underpowered (a point acknowledged by the authors). However this is very important and useful information for resource-limited settings.

Emergency use of prethawed Group A plasma in trauma patients
J Trauma Acute Care Surg. 2013 Jan;74(1):69-74


BACKGROUND: Massive transfusion protocols lead to increased use of the rare universal plasma donor, Type AB, potentially limiting supply. Owing to safety data, with a goal of avoiding shortages, our blood bank exploited Group A rather than AB for all emergency release plasma transfusions. We hypothesized that ABO-incompatible plasma transfusions had mortality similar to ABO-compatible transfusions.

METHODS: Review of all trauma patients receiving emergency release plasma (Group A) from 2008 to 2011 was performed. ABO compatibility was determined post hoc. Deaths before blood typing were eliminated. p < 0.05 was considered statistically significant.

RESULTS: Of the 254 patients, 35 (14%) received ABO-incompatible and 219 (86%) received ABO-compatible transfusions. There was no difference in age (56 years vs. 59 years), sex (63% vs. 63% male), Injury Severity Score (ISS) (25 vs. 22), or time spent in the trauma bay (24 vs. 26.5 minutes). Median blood product units transfused were similar: emergency release plasma (2 vs. 2), total plasma at 24 hours (6 vs. 4), total red blood cells at 24 hours (5 vs. 4), plasma-red blood cells at 24 hours (1.3:1 vs. 1.1:1), and plasma deficits at 24 hours (2 vs. 1). Overall complications were similar (43% vs. 35%) as were rates of possible transfusion-related acute lung injury (2.9% vs. 1.8%), acute lung injury (3.7% vs. 2.5%), adult respiratory distress syndrome (2.9% vs. 1.8%), deep venous thrombosis (2.9% vs. 4.1%), pulmonary embolism (5.8% vs. 7.3%), and death (20% vs. 22%). Ventilator (6 vs. 3), intensive care unit (4 vs. 3), and hospital days (9 vs. 7) were similar. There were no hemolytic reactions. Mortality was significantly greater for the patients who received incompatible plasma if concurrent with a massive transfusion (8% vs. 40%, p = 0.044). Group AB plasma use was decreased by 96.6%.

CONCLUSION: Use of Group A for emergency release plasma resulted in ABO-incompatible transfusions; however, this had little effect on clinical outcomes. Blood banks reticent to adopt massive transfusion protocols owing to supply concerns may safely use plasma Group A, expanding the pool of emergency release plasma donors.

LEVEL OF EVIDENCE: Therapeutic study, level IV; prognostic study, level III.

Hydroxyethyl Starch vs Saline

October 20, 2012 by  
Filed under Acute Med, All Updates, ICU, Resus

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Another nail in the coffin of starch solutions for critical care patients was banged in by Prof Myburgh and colleagues who published the results of the CHEST randomised trial this week(1). 7000 Australasian ICU patients received either 6% HES (130/0.4) in 0.9% saline (HES group) or 0.9% saline (saline group). There was no difference in mortality but there was more renal dysfunction, rash, and pruritis in the HES group.

This can be combined with another recent starch vs crystalloid paper demonstrating adverse outcomes from starch(2) to make the case that there is no role for these pharmaceuticals in resuscitation or critical care.

1. Hydroxyethyl Starch or Saline for Fluid Resuscitation in Intensive Care
N Engl J Med. 2012 Oct 17. [Epub ahead of print] Free Full Text


Background The safety and efficacy of hydroxyethyl starch (HES) for fluid resuscitation have not been fully evaluated, and adverse effects of HES on survival and renal function have been reported.

Methods We randomly assigned 7000 patients who had been admitted to an intensive care unit (ICU) in a 1:1 ratio to receive either 6% HES with a molecular weight of 130 kD and a molar substitution ratio of 0.4 (130/0.4, Voluven) in 0.9% sodium chloride or 0.9% sodium chloride (saline) for all fluid resuscitation until ICU discharge, death, or 90 days after randomization. The primary outcome was death within 90 days. Secondary outcomes included acute kidney injury and failure and treatment with renal-replacement therapy.

Results A total of 597 of 3315 patients (18.0%) in the HES group and 566 of 3336 (17.0%) in the saline group died (relative risk in the HES group, 1.06; 95% confidence interval [CI], 0.96 to 1.18; P=0.26). There was no significant difference in mortality in six predefined subgroups. Renal-replacement therapy was used in 235 of 3352 patients (7.0%) in the HES group and 196 of 3375 (5.8%) in the saline group (relative risk, 1.21; 95% CI, 1.00 to 1.45; P=0.04). In the HES and saline groups, renal injury occurred in 34.6% and 38.0% of patients, respectively (P=0.005), and renal failure occurred in 10.4% and 9.2% of patients, respectively (P=0.12). HES was associated with significantly more adverse events (5.3% vs. 2.8%, P<0.001).

Conclusions In patients in the ICU, there was no significant difference in 90-day mortality between patients resuscitated with 6% HES (130/0.4) or saline. However, more patients who received resuscitation with HES were treated with renal-replacement therapy

2. Hydroxyethyl starch 130/0.42 versus Ringer’s acetate in severe sepsis
N Engl J Med. 2012 Jul 12;367(2):124-34


BACKGROUND: Hydroxyethyl starch (HES) [corrected] is widely used for fluid resuscitation in intensive care units (ICUs), but its safety and efficacy have not been established in patients with severe sepsis.

METHODS: In this multicenter, parallel-group, blinded trial, we randomly assigned patients with severe sepsis to fluid resuscitation in the ICU with either 6% HES 130/0.42 (Tetraspan) or Ringer’s acetate at a dose of up to 33 ml per kilogram of ideal body weight per day. The primary outcome measure was either death or end-stage kidney failure (dependence on dialysis) at 90 days after randomization.

RESULTS: Of the 804 patients who underwent randomization, 798 were included in the modified intention-to-treat population. The two intervention groups had similar baseline characteristics. At 90 days after randomization, 201 of 398 patients (51%) assigned to HES 130/0.42 had died, as compared with 172 of 400 patients (43%) assigned to Ringer’s acetate (relative risk, 1.17; 95% confidence interval [CI], 1.01 to 1.36; P=0.03); 1 patient in each group had end-stage kidney failure. In the 90-day period, 87 patients (22%) assigned to HES 130/0.42 were treated with renal-replacement therapy versus 65 patients (16%) assigned to Ringer’s acetate (relative risk, 1.35; 95% CI, 1.01 to 1.80; P=0.04), and 38 patients (10%) and 25 patients (6%), respectively, had severe bleeding (relative risk, 1.52; 95% CI, 0.94 to 2.48; P=0.09). The results were supported by multivariate analyses, with adjustment for known risk factors for death or acute kidney injury at baseline.

CONCLUSIONS: Patients with severe sepsis assigned to fluid resuscitation with HES 130/0.42 had an increased risk of death at day 90 and were more likely to require renal-replacement therapy, as compared with those receiving Ringer’s acetate.

Hypotonic Versus Isotonic Fluids After Surgery for Children

June 15, 2012 by  
Filed under All Updates, ICU, Kids, Resus

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Kids in hospital with injury, infection or other illness, and those undergoing the physiological stress of surgery, produce (appropriately) elevated antidiuretic hormone levels which contribute to the risk of hyponatraemia by impairing free water excretion in the kidney.

Deaths have occurred on general paediatric and surgery wards when fluid regimens containing low concentrations of sodium (classically 0.18% or 0.225% NaCl) have resulted in hyponatraemia in children without adequate electrolyte monitoring, leading some bodies to recommend at least 0.45% NaCl solutions for maintenance fluid therapy in children.

However two recent studies1,2 on postoperative children show an increased risk of hyponatraemia even with 0.45% saline, when compared with 0.9% saline or Hartmann’s solution (Hartmann’s is similar – almost identical – to Ringer’s lactate).

I like the fact that paediatricians used Hartmann’s in one of these studies1. I have worked with several paediatricians who never use Hartmann’s, either from lack of experience or because of concern about its lactate content (not appreciating the lactate is metabolised by the liver to bicarbonate).
This is ironic, since Alexis Hartmann (1898–1964) was a paediatrician.

Want more fluid therapy irony? The ‘balanced salt solution’ used by Brits and Australasians is Hartmann’s solution – named after an American. The one used by Americans is Lactated Ringer’s solution – named after the British physician Sydney Ringer (1834-1910).

Medical history enthusiasts can read more about Hartmann and Ringer here.

1. A randomised controlled trial of Hartmann’s solution versus half normal saline in postoperative paediatric spinal instrumentation and craniotomy patients.
Arch Dis Child. 2012 Jun;97(6):491-6


OBJECTIVE: To compare the difference in plasma sodium at 16-18 h following major surgery in children who were prescribed either Hartmann’s and 5% dextrose or 0.45% saline and 5% dextrose.

DESIGN: A prospective, randomised, open label study.

SETTING: The paediatric intensive care unit (650 admissions per annum) in a tertiary children’s hospital in Brisbane, Australia.

PATIENTS: The study group comprised 82 children undergoing spinal instrumentation, craniotomy for brain tumour resection, or cranial vault remodelling.

INTERVENTIONS: Patients received either Hartmann’s and 5% dextrose at full maintenance rate or 0.45% saline and 5% dextrose at two-thirds maintenance rate.

MAIN OUTCOMES MEASURES: Primary outcome measure: plasma sodium at 16-18 h postoperatively; secondary outcome measure: number of fluid boluses administered.

RESULTS: Mean postoperative plasma sodium levels of children receiving 0.45% saline and 5% dextrose were 1.4 mmol/l (95% CI 0.4 to 2.5) lower than those receiving Hartmann’s and 5% dextrose (p=0.008). In the 0.45% saline group, seven patients (18%) became hyponatraemic (Na <135 mmol/l) at 16-18 h postoperatively; in the Hartmann’s group no patient became hyponatraemic (p=0.01). No child in either fluid group became hypernatraemic.

CONCLUSIONS: The postoperative fall in plasma sodium was smaller in children who received Hartmann’s and 5% dextrose compared to those who received 0.45% saline and 5% dextrose. It is suggested that Hartmann’s and 5% dextrose should be administered at full maintenance rate postoperatively to children who have undergone major surgery in preference to hypotonic fluids.

2. Hypotonic versus isotonic maintenance fluids after surgery for children: a randomized controlled trial
Pediatrics. 2011 Nov;128(5):857-66.


OBJECTIVE: The objective of this randomized controlled trial was to evaluate the risk of hyponatremia following administration of a isotonic (0.9% saline) compared to a hypotonic (0.45% saline) parenteral maintenance solution (PMS) for 48 hours to postoperative pediatric patients.

METHODS: Surgical patients 6 months to 16 years of age with an expected postoperative stay of >24 hours were eligible. Patients with an uncorrected baseline plasma sodium level abnormality, hemodynamic instability, chronic diuretic use, previous enrollment, and those for whom either hypotonic PMS or isotonic PMS was considered contraindicated or necessary, were excluded. A fully blinded randomized controlled trial was performed. The primary outcome was acute hyponatremia. Secondary outcomes included severe hyponatremia, hypernatremia, adverse events attributable to acute plasma sodium level changes, and antidiuretic hormone levels.

RESULTS: A total of 258 patients were enrolled and assigned randomly to receive hypotonic PMS (N = 130) or isotonic PMS (N = 128). Baseline characteristics were similar for the 2 groups. Hypotonic PMS significantly increased the risk of hyponatremia, compared with isotonic PMS (40.8% vs 22.7%; relative risk: 1.82 [95% confidence interval: 1.21-2.74]; P = .004). Admission to the pediatric critical care unit was not an independent risk factor for the development of hyponatremia. Isotonic PMS did not increase the risk of hypernatremia (relative risk: 1.30 [95% confidence interval: 0.30-5.59]; P = .722). Antidiuretic hormone levels and adverse events were not significantly different between the groups.

CONCLUSION: Hypotonic Versus Isotonic Maintenance Fluids After Surgery for Children: A Randomized Controlled Trial.

Prehospital burn management in a combat zone.

May 18, 2012 by  
Filed under All Updates, EMS, Guidelines, Resus, Trauma

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A military study revealed troops suffering from severe burns tended to receive either no prehospital fluid or too much fluid1.

The authors point out some practical realities and an attempted solution:


For a medic potentially treating multiple casualties at once in a hostile environment, the calculation of the modified Brooke or Parkland formula may be unrealistic prior to beginning fluid resuscitation in the prehospital setting.

The USAISR’s Rule of 10 is a simplified formula to guide the initial fluid resuscitation of a burn victim. The burn size is estimated to the nearest 10% TBSA. For patients weighing 40 to 80 kg, the burn size is then multiplied by 10 to give the initial fluid rate in milliliters per hour. The rate is increased by 100 mL/hour for every 10 kg above 80 kg in terms of the patient’s weight. For the majority of adult burn patients, the Rule of 10 approximates the initial fluid rate within accepted ABA guidelines.


A previous study on the rule of 10 showed it provided an estimate that fell between the modified Brooke and Parkland estimates 87.8% of the time, less than the modified Brooke <12% of the time, and hardly ever (>1%) exceeded the Parkland estimate2.


OBJECTIVE: The purpose of this article is to provide a descriptive study of the management of burns in the prehospital setting of a combat zone.

METHODS: A retrospective chart review was performed of U.S. casualties with >20% total-body-surface-area thermal burns, transported from the site of injury to Ibn Sina Combat Support Hospital (CSH) between January 1, 2006, and August 30, 2009.

RESULTS: Ibn Sina CSH received 225 burn casualties between January 2006 and August 2009. Of these, 48 met the inclusion criteria. The mean Injury Severity Score was 31.7 (range 4 to 75). Prehospital vascular access was obtained in 24 casualties (50%), and 20 of the casualties received fluid resuscitation. Out of the 48 casualties enrolled, 28 (58.3%) did not receive prehospital fluid resuscitation. Of the casualties who received fluid resuscitation, nearly all received volumes in excess of the guidelines established by the American Burn Association and those recommended by the Committee for Tactical Combat Casualty Care. With regard to pain management in the prehospital setting, 13 casualties (27.1%) received pain medication.

CONCLUSIONS: With regard to the prehospital fluid resuscitation of primary thermal injury in the combat zone, two extremes were noted. The first group did not receive any fluid resuscitation; the second group was resuscitated with fluid volumes higher than those expected if established guidelines were utilized. Pain management was not uniformly provided to major burn casualties, even in several with vascular access. These observations support improved education of prehospital personnel serving in a combat zone.

1. Prehospital burn management in a combat zone
Prehosp Emerg Care, 2012 vol. 16 (2) pp. 273-276

2. Simple derivation of the initial fluid rate for the resuscitation of severely burned adult combat casualties: in silico validation of the rule of 10
J Trauma. 2010 Jul;69 Suppl 1:S49-54

Passive leg raise predicted fluid responsiveness in kids

May 5, 2012 by  
Filed under All Updates, ICU, Kids

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Passive leg raising (PLR) is a great ‘free reversible fluid challenge’ to see if a shocked or hypotensive patient is likely to respond to volume therapy. A new study assesses its applicability in children.

PLR predicted fluid responders with 85% specificity but a lack of response did not rule out fluid responsiveness. Also, the effect of the PLR on cardiac index measured by echocardiography was the only way of predicting response – there was no relation to the more easily monitored effects of PLR on systolic blood pressure or heart rate.

Want to learn how to measure cardiac output using ultrasound? Mike Mallin from the Emergency Ultrasound Podcast shows you how here


OBJECTIVE: Fluid challenge is often used to predict fluid responsiveness in critically ill patients. Inappropriate fluid expansion can lead to some unwanted side effects; therefore, we need a noninvasive predictive parameter to assess fluid responsiveness. We want to assess the hemodynamic parameter changes after passive leg raising, which can mimic fluid expansion, to predict fluid responsiveness in pediatric intensive care unit patients and to get a cutoff value of cardiac index in predicting fluid responsiveness in pediatric patients.

DESIGN: Nonrandomized experimental study.

SETTING: Tertiary academic pediatric intensive care.

PATIENTS: Children admitted to pediatric intensive care.

INTERVENTION: Hemodynamic parameters were assessed at baseline, after passive leg raising, at second baseline, and after volume expansion (10 mL/kg normal saline infusion over 15 mins).

MEASUREMENTS AND MAIN RESULTS: We measured the heart rate, systolic blood pressure, and stroke volume and cardiac index using Doppler echocardiography. The hemodynamic parameter changes induced by passive leg raising were monitored. Among 40 patients included in the study, 20 patients had a cardiac index increase of ≥10% after volume expansion (responders). Changes in heart rate, systolic blood pressure, and stroke volume after passive leg raising did not significantly relate to the response to volume expansion. There was significant relation between changes in cardiac index to predict fluid responsiveness (p = .012, r = .22, 95% confidence interval 1.529 to 31.37). A cardiac index increase by ≥10% induced by passive leg raising predicted preload-dependent status with sensitivity of 55% and specificity of 85% (area under the curve 0.71 ± 0.084, 95% confidence interval 0.546-0.874).

CONCLUSION: The concomitant measurements in cardiac index changes after the passive leg raising maneuver can be helpful in predicting who might have an increase in cardiac index with subsequent fluid resuscitation.

The role of passive leg raising to predict fluid responsiveness in pediatric intensive care unit patients.
Pediatric Critical Care Medicine. 13(3):e155-e160, May 2012

Colloid volume therapy for critically ill patients

March 5, 2012 by  
Filed under All Updates, Guidelines, ICU, Resus

The European Society of Intensive Care Medicine has produced a consensus statement on colloid volume therapy for critically ill patients, published in this month’s Intensive Care Medicine.
Curiously, the full text document is not yet availablle on ESICM’s website, but I found this presentation summarising the work by one the authors (Richard Beale):


PURPOSE: Colloids are administered to more patients than crystalloids, although recent evidence suggests that colloids may possibly be harmful in some patients. The European Society of Intensive Care Medicine therefore assembled a task force to compile consensus recommendations based on the current best evidence for the safety and efficacy of the currently most frequently used colloids-hydroxyethyl starches (HES), gelatins and human albumin.

METHODS: Meta-analyses, systematic reviews and clinical studies of colloid use were evaluated for the treatment of volume depletion in mixed intensive care unit (ICU), cardiac surgery, head injury, sepsis and organ donor patients. Clinical endpoints included mortality, kidney function and bleeding. The relevance of concentration and dosage was also assessed. Publications from 1960 until May 2011 were included. The quality of available evidence and strength of recommendations were based on the Grading of Recommendations Assessment, Development, and Evaluation (GRADE) approach.

RECOMMENDATIONS AND CONCLUSIONS: We recommend not to use HES with molecular weight ≥200 kDa and/or degree of substitution >0.4 in patients with severe sepsis or risk of acute kidney injury and suggest not to use 6% HES 130/0.4 or gelatin in these populations. We recommend not to use colloids in patients with head injury and not to administer gelatins and HES in organ donors. We suggest not to use hyperoncotic solutions for fluid resuscitation. We conclude and recommend that any new colloid should be introduced into clinical practice only after its patient-important safety parameters are established.

Consensus statement of the ESICM task force on colloid volume therapy in critically ill patients
Intensive Care Med. 2012 Mar;38(3):368-83

Update September 2012:
An RCT showed patients with severe sepsis assigned to fluid resuscitation with HES 130/0.42 had an increased risk of death at day 90 and were more likely to require renal-replacement therapy, as compared with those receiving Ringer’s acetate. Read more about the trial here
Hydroxyethyl Starch 130/0.42 versus Ringer’s Acetate in Severe Sepsis
N Engl J Med. 2012 Jul 12;367(2):124-34

Australian intensivist John Myburgh gives a great summary of Fluid Therapy in critical care here

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