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In their systematic review Schierhout and Roberts (1) selected 19 trials with published mortality data (although mortality was recorded at the end of various follow up times) to determine the effect on mortality of resuscitation with crystalloid or colloid solutions. They concluded the continued use of colloids for volume replacement could not be supported in critically ill patients. On first inspection of the table it is clear that the colloid solutions used were predominately albumin or dextran, colloid concentrations varied between the studies and the solvent could have been isotonic or hypertonic crystalloid.
When accepting such a variety of treatments and a variety of controls in a meta-analysis, it is surely not surprising that no difference is found between groups. The conclusion should have been that dextran or albumin cannot be recommended rather than all colloids since most of the artificial plasma substitutes were not part of this study. A total of 1315 patients were included in the meta-analysis. In 381 cases the colloid was an albumin solution, in 22 gelatin, in 41 hydroxyethyl starch and in 652 dextran. Mixed colloids were used in 66 patients and plasma in 153. Mortality excess in the colloid groups only occurred in three studies (2,3,4) of which one used albumin and two used dextran (both dextran studies from the same centre). With such factors taken into account the reported mortality excess of 4% is difficult to interpret and cannot be applied to all colloids.
If we were to perform a randomized controlled trial of colloid versus crystalloid we would need to study 6584 patients to detect an excess mortality of 4% over a control level of 20% assuming a type I error risk of 5% and a type II error risk of 2.5%. To detect equivalence we would need 4611 patients assuming a mortality of 20% and 4% being the greatest possible difference in mortality being accepted as equivalent. This of course would be a trial that takes out the confounding factors of different colloids and different crystalloids spread amongst the control and protocol arms.
The interpretation of the meta-analysis is further confused by the sub-group analysis. The authors separate trials into groups based on type of injury (using the term injury to mean insult). If this is clinically justified on the basis that these insults are really different, how can it be justified to combine the groups for the overall analysis? If some insults do better with crystalloid and some do better with colloid, the combination of the sub-groups should be expected to remove the treatment effect.
Finally, it is as well to remember that the choice of fluid is just one factor in the complex therapeutic strategy required in the management of the critically ill. Whether crystalloid or colloid is ultimately cheaper must depend on how they affect other parts of the therapeutic strategy and what volumes of each are required. If fluid resuscitation involves a fluid challenge regimen (fluid given according to repeated assessment of need) then we require a known blood volume increment in order to assess the haemodynamic response. Colloid clearly has an advantage here in that the immediate response will be closely related to the volume infused. Failure to achieve a haemodynamic response with crystalloid may be due to excessive capillary leak. In this respect we are not using colloid as a drug to reduce mortality; rather we are using a particular property as part of a much wider therapeutic strategy. Randomised trials are difficult in this situation since the way something is used is determined by the user with knowledge of what he is using.
References
1. Schierhout G, Roberts I. Fluid resuscitation with colloid or crystalloid solutions in critically ill patients: a systematic review of randomised trials BMJ 1998;316:961-964
2. Goodwin CW, Dorethy J, Lam V, Pruitt BA Jr. Randomized trial of efficacy of crystalloid and colloid resuscitation on hemodynamic response and lung water following thermal injury. Ann Surg 1983;197:520-31.
3. Vassar MJ, Fischer RP, O'Brien PE, et al. A multicenter trial for resuscitation of injured patients with 7.5% sodium chloride. The effect of added dextran 70. The Multicenter Group for the Study of Hypertonic Saline in Trauma Patients. Arch Surg 1993;128:1003-11.
4. Vassar MJ, Perry CA, Holcroft JW. Prehospital resuscitation of hypotensive trauma patients with 7.5% NaCl versus 7.5% NaCl with added dextran: a controlled trial. J Trauma 1993;34:622-32.
Mortality is the wrong end-point
In their systematic review Schierhout and Roberts (1) selected 19 trials with published mortality data (although mortality was recorded at the end of various follow up times) to determine the effect on mortality of resuscitation with crystalloid or colloid solutions. They concluded the continued use of colloids for volume replacement could not be supported in critically ill patients. On first inspection of the table it is clear that the colloid solutions used were predominately albumin or dextran, colloid concentrations varied between the studies and the solvent could have been isotonic or hypertonic crystalloid.
When accepting such a variety of treatments and a variety of controls in a meta-analysis, it is surely not surprising that no difference is found between groups. The conclusion should have been that dextran or albumin cannot be recommended rather than all colloids since most of the artificial plasma substitutes were not part of this study. A total of 1315 patients were included in the meta-analysis. In 381 cases the colloid was an albumin solution, in 22 gelatin, in 41 hydroxyethyl starch and in 652 dextran. Mixed colloids were used in 66 patients and plasma in 153. Mortality excess in the colloid groups only occurred in three studies (2,3,4) of which one used albumin and two used dextran (both dextran studies from the same centre). With such factors taken into account the reported mortality excess of 4% is difficult to interpret and cannot be applied to all colloids.
If we were to perform a randomized controlled trial of colloid versus crystalloid we would need to study 6584 patients to detect an excess mortality of 4% over a control level of 20% assuming a type I error risk of 5% and a type II error risk of 2.5%. To detect equivalence we would need 4611 patients assuming a mortality of 20% and 4% being the greatest possible difference in mortality being accepted as equivalent. This of course would be a trial that takes out the confounding factors of different colloids and different crystalloids spread amongst the control and protocol arms.
The interpretation of the meta-analysis is further confused by the sub-group analysis. The authors separate trials into groups based on type of injury (using the term injury to mean insult). If this is clinically justified on the basis that these insults are really different, how can it be justified to combine the groups for the overall analysis? If some insults do better with crystalloid and some do better with colloid, the combination of the sub-groups should be expected to remove the treatment effect.
Finally, it is as well to remember that the choice of fluid is just one factor in the complex therapeutic strategy required in the management of the critically ill. Whether crystalloid or colloid is ultimately cheaper must depend on how they affect other parts of the therapeutic strategy and what volumes of each are required. If fluid resuscitation involves a fluid challenge regimen (fluid given according to repeated assessment of need) then we require a known blood volume increment in order to assess the haemodynamic response. Colloid clearly has an advantage here in that the immediate response will be closely related to the volume infused. Failure to achieve a haemodynamic response with crystalloid may be due to excessive capillary leak. In this respect we are not using colloid as a drug to reduce mortality; rather we are using a particular property as part of a much wider therapeutic strategy. Randomised trials are difficult in this situation since the way something is used is determined by the user with knowledge of what he is using.
References
1. Schierhout G, Roberts I. Fluid resuscitation with colloid or crystalloid solutions in critically ill patients: a systematic review of randomised trials BMJ 1998;316:961-964
2. Goodwin CW, Dorethy J, Lam V, Pruitt BA Jr. Randomized trial of efficacy of crystalloid and colloid resuscitation on hemodynamic response and lung water following thermal injury. Ann Surg 1983;197:520-31.
3. Vassar MJ, Fischer RP, O'Brien PE, et al. A multicenter trial for resuscitation of injured patients with 7.5% sodium chloride. The effect of added dextran 70. The Multicenter Group for the Study of Hypertonic Saline in Trauma Patients. Arch Surg 1993;128:1003-11.
4. Vassar MJ, Perry CA, Holcroft JW. Prehospital resuscitation of hypotensive trauma patients with 7.5% NaCl versus 7.5% NaCl with added dextran: a controlled trial. J Trauma 1993;34:622-32.
Competing interests: No competing interests