M Grounds

Recombinant factor VIIa (rFVIIa) and its use in severe bleeding in surgery and trauma: a review

Haemorrhage is a potential complication of any surgical procedure, presenting a major challenge to the surgeon and anaesthetist. In addition, uncontrolled bleeding accounts for at least 40% of the mortality associated with military and civilian trauma. Despite the widespread availability of standard interventions for the control of bleeding in such circumstances, there still remains an urgent need for an effective haemostatic agent that is safe, easy to use, and able to enhance local thrombotic processes without causing generalised arterial or venous thrombosis. Recombinant factor VIIa (rFVIIa; NovoSeven) has been successfully used in the management of haemophilia patients with inhibitors for many years. This review will explore its use in the control of surgery- and trauma-associated haemorrhage in patients without pre-existing coagulopathy, and will highlight the growing realisation that rFVIIa may have a major role not only as a treatment for haemophilia, but also as a universal haemostatic agent. This paper will also briefly explore those unanswered questions that should be resolved by future trials aiming to further clarify the safety, efficacy, and optimal dosing strategies of rFVIIa in the surgical and trauma settings.

Unanswered questions from Corticus and pragmatic suggestions

Professor Vincent, in an eloquent commentary in Critical Care, calls for a further trial into supraphysiological cortico-steroid therapy in vasopressor-resistant shock [1]. Together with editorials in several of the intensive care journals, he has pointed out many of the shortcomings in the Corticus trial [2]. We would like to add to this chorus by posing a further question to the authors and putting forward some suggestions. Regrettably, we are prohibited from addressing these directly due to the Letters policy of the journal in which the original paper was published. Data from numerous sources suggest that the earlier shock is reversed, the better the outcome – be it mortality, morbidity, length of stay or other surrogate endpoints. In the Corticus study, the median time to shock reversal was 2 to 3 days shorter in the hydrocortisone group (see Table ​Table1).1). Despite this, no outcome improvement was demonstrated. No investigation, or explanation, of this apparent discrepancy has been forthcoming. Sequential Organ Failure Assessment scores were performed at the time of study enrolment, but no serial Sequential Organ Failure Assessment score data are presented. If available, these data would be intriguing. Table 1 Time to shock reversal data from the Corticus study [2] Following the publication of the Corticus data, a consensus statement regarding the diagnosis and management of corticosteroid insufficiency in critically ill adult patients has been published [3]. Together with a detailed review by Dickstein and Saiegh [4], this statement suggests a working diagnostic paradigm. However, we would like to suggest the following three pragmatic definitions of functional hypoadrenalism, which future trial designers might with wish to consider and which we currently employ. First, patients with septic shock requiring high-dose vaso-pressors – defined as requiring ≥ 0.2 μg/kg/minute norepinephrine (or equivalent), who are not volume responsive (defined as a ≥ 10% increase in stroke volume following a 3 ml/kg fluid bolus administered in ≤ 5 min) and who are hyperdynamic (defined as a cardiac index ≥ 2.8 l/min/m2). Patients with evidence of acute myocardial depression or chronic insufficiency should be considered separately. Second, patients who, having been stable for ≥ 2 hours on a dose of vasopressor, develop increasing dose requirements (≥ 20% increase), are unresponsive to a volume bolus (as above) and are hyperdynamic (as above). Third, patients whose dose of vasopressor cannot be weaned ≥ 24 hours following initiation of appropriate broad-spectrum antimicrobial therapy and/or effective source control. Furthermore, this therapy should be withdrawn from patients who fail to demonstrate a ≥ 20% decrease in vasopressor requirement to maintain the same mean arterial pressure 60 minutes after the initial dose of hydrocortisone. Due to the pharmacokinetics of hydrocortisone, we favour a 100 mg intravenous bolus followed immediately by initiation of a 10 mg/hour intravenous infusion. Finally, we would like to promote two recently published papers that offer useful insights into the pharmacodynamics of supraphysiological steroid therapy in vasopressor-resistant shock. Firstly, Druce and colleagues make a convincing argument that the principal effect of hydrocortisone is as a mineralocorticoid and not as an anti-inflammatory [5]. Secondly, Kaufman and colleagues [6] found that hydrocortisone administered as described above does have some arguably clinically valuable anti-inflammatory effects but, in addition, enhances neutrophil phagocytosis. This has led us to conclude that, in the absence of a systemic form of fludrocortisone and with the unreliable enteral absorption of drugs, systemic hydrocortisone monotherapy at optimal mineralocorticoid doses should be the therapy of choice.

A rare presentation of micro-angiopathic haemolytic anaemia in a critically ill patient: a case report

A 36-year-old woman presents to hospital peri-arrest with hypertension, sustained loss of consciousness following a tonic clonic seizure and a micropathic haemolytic anaemia on blood film. After initial resuscitation, more specialised treatment was instigated as the diagnosis became clearer but all was not as it first seemed. This case demonstrates the importance of re-examination, especially in the critically ill, in conjunction with unusual laboratory tests in order to eventually reach a rare diagnosis of a rare presentation.