Pulmonary artery flow catheters for directing management in pre‐eclampsia

Abstract

Background

Gestational hypertension and pre‐eclampsia can cause fluid shifts. Pulmonary oedema and renal failure can result from these shifts. Fluid management is crucial in managing pre‐eclampsia, especially in the context of pulmonary oedema and renal failure. Pulmonary artery catheterisation may be a method of effectively monitoring fluid status and thus aid in the management of renal failure and pulmonary oedema in the context of pre‐eclampsia.

Objectives

To assess the safety and efficacy of pulmonary flow catheters in women with severe pre‐eclampsia in preventing and managing of renal failure and pulmonary oedema or both.

Search methods

We searched the Cochrane Pregnancy and Childbirth Group's Trials Register (30 April 2012).

Selection criteria

Randomised trials evaluating the use of the pulmonary artery catheterisation in the management of pre‐eclamptic and eclamptic antepartum, intrapartum and postpartum women.

Data collection and analysis

We did not identify any randomised controlled studies.

Main results

There are no included studies.

Authors' conclusions

There is currently no evidence from randomised controlled trials supporting the use of the pulmonary artery catheters. Fluid management in pre‐eclampsia, especially in the context of preventing or managing renal failure and pulmonary oedema, remains an important issue. Randomised trials dealing with this intervention are needed, however, we do recognise the difficulty in performing randomised trials due to the invasive nature of the procedure and skills involved in inserting a pulmonary flow catheter.

Plain language summary

Pulmonary artery catheters for directing management in condition associated with high blood pressure during pregnancy

Pre‐eclampsia (a condition associated with high blood pressure during pregnancy) or toxaemia affects a significant number of pregnancies and is a major cause of serious illness and even death of mothers and babies during pregnancy and shortly after. Pre‐eclampsia can cause decreased blood flow to the kidneys resulting in kidney failure and fluid accumulation in the lungs and other organs. Managing fluid shifts is, thus, crucial to preventing and managing such complications. The pulmonary artery catheter is one method of monitoring fluid status. The pulmonary artery catheter is a special device placed inside of the pulmonary artery for  measurement of pressures in the different parts of heart, which helps to monitor the fluid balance in the body. Although it seem to be the most reliable method for monitoring of fluid shifts, the placement of pulmonary artery catheters may be associated with the highest risk of complications. No randomised trials involving pulmonary artery catheterisation were found and, thus, there is no robust data to support or disregard the use of this intervention. The complexity of this procedure and the skills needed to perform it may have affected the lack of randomised trials. Nevertheless, fluid management is still an important issue in managing and preventing kidney failure and accumulation of fluid in the lungs and other organs in the context of pre‐eclampsia and pulmonary artery catheterisation is a potential technique for this. We think that further research, especially randomised trials, is needed.

Background

Description of the condition

Pre‐eclampsia ('toxaemia') is defined as hypertension accompanied by proteinuria (protein in the urine) (NHBPEP 2000). It usually occurs during the second half of pregnancy and complicates 2% to 8% of pregnancies (WHO 1988). Mild pre‐eclampsia has an incidence of 10% and severe pre‐eclampsia has an incidence of 1%. Two of the serious complications of severe pre‐eclampsia are pulmonary oedema (fluid in the lungs) and renal failure. According to Sibai and co‐authors, the incidence of pulmonary oedema is 2.9% in pre‐eclamptic patients (Sibai 1987) while that of renal failure is around 7% in severe pre‐eclampsia with HELLP (haemolysis elevated liver enzymes and low platelets) syndrome. The analysis of the causes of hypertensive death shows that cerebrovascular haemorrhage is the leading cause of deaths, most likely due to presenting as an unequivocal clinical event. When assessing deaths due to cardiac, renal and pulmonary failure, it is evident that pulmonary oedema and respiratory distress may be the cause of death. Therefore, the need for careful fluid management of women with pre‐eclampsia would seem an appropriate policy. Invasive monitoring may be especially important to prevent pulmonary oedema in circumstances where fluid administration is necessary, such as in oliguric (decrease in urine output) patients and those who have pre‐eclampsia combined with obstetric haemorrhage. Another indication for invasive monitoring may be management of pulmonary oedema due to pre‐eclampsia. Invasive monitoring is also important in fluid management of women with renal failure, which is critical in the prevention of long‐term renal damage.

This protocol has been developed using the Cochrane Pregnancy and Childbirth Group's generic protocol for treating pre‐eclampsia and its consequences (Duley 2009).

Definitions and classification

Pre‐eclampsia is part of a spectrum of conditions known as the hypertensive disorders of pregnancy. These disorders have a continuum with normal pregnancy. During normal pregnancy there is enormous maternal physiological adaptation to accommodate the growing fetus and placenta. For example, cardiac output increases by about 40% in the first trimester. In contrast, blood pressure remains relatively unchanged in the first trimester, falling by about 5 mmHg to 10 mmHg in the second trimester, and rising back to pre‐pregnancy levels by term. Cardiac output is influenced by peripheral resistance and blood pressure. As normal pregnancy is associated with increased cardiac output and normal or slightly lowered blood pressure, peripheral resistance falls (De Swiet 2002). Changes in kidney function also occur in normal pregnancy, with increased protein excretion especially in the third trimester. In normal pregnancy, up to 300 mg protein in 24 hours' output of urine is accepted as normal. Classification and definition of the hypertensive disorders of pregnancy have, in the past, been controversial. More recently, there has been a shift towards agreeing on and accepting standard definitions, and ensuring they are relevant for clinical practice (Brown 2001). What follows is based on current consensus.

Definition of hypertension

Hypertension in pregnancy is usually defined as systolic blood pressure of at least 140 mmHg, diastolic blood pressure of at least 90 mmHg, or both. Any rise in blood pressure should be confirmed by a second measurement, ideally at least four hours later. Because of cardiovascular changes, automated blood pressure monitors systematically underestimate blood pressure in pregnancy and pre‐eclampsia. If used, they should be calibrated regularly against a mercury sphygmomanometer (Shennan 2003). The debate over which auscultatory sound to use for assessment of diastolic blood pressure, muffling (Korotkoff phase IV) or disappearance (Korotkoff phase V), has been resolved, and Korotkoff V is now recommended as more reliable (Brown 2001).

Definition of proteinuria

Proteinuria during pregnancy is defined as 300 mg protein, or more, in 24 hours (Brown 2001). In a single midstream urine sample, this usually correlates with 30 mg/dL, 1+ or more on a dipstick, or a spot urine protein/creatinine ratio of at least 30 mg/mmol.

Categories of hypertensive disorders of pregnancy

Four main categories are now widely agreed.

(1) Gestational hypertension

This is hypertension detected for the first time during the second half of pregnancy (after 20 weeks of gestation) in the absence of proteinuria. It typically resolves within three months of birth.

(2) Pre‐eclampsia/eclampsia

Pre‐eclampsia is defined as hypertension and proteinuria detected for the first time in the second half of pregnancy (after 20 weeks of gestation). Eclampsia is the occurrence of seizures in a woman with pre‐eclampsia. There is no widely accepted definition of severe pre‐eclampsia. Nevertheless, the following are widely regarded as features of severe disease: severe hypertension (blood pressure at least 160 mmHg systolic, or 110 mmHg diastolic), severe proteinuria (usually at least 3 g (range 2 g to 5 g) protein in 24 hours, or 3+ on dipstick), reduced urinary volume (less than 500 mL in 24 hours), neurological disturbances such as headache, visual disturbances, and exaggerated tendon reflexes, upper abdominal pain, pulmonary oedema, impaired liver function tests (at twice the upper limit of normal, or about 70 or more), high serum creatinine (more than 60 μmol/L), low platelets (less than 100,000/mm³). Some also add intrauterine growth restriction as a possible criteria for severe pre‐eclampsia (Brown 2001; NHBPEP 2000).

(3) Chronic hypertension

This is hypertension known to be present before pregnancy, or detected before 20 weeks of gestation. It is essential hypertension if there is no underlying cause, and secondary hypertension if there is an underlying cause such as renal, cardiac, or endocrine disease. ‘Chronic’ hypertension may present for the first time as gestational hypertension. Hence, gestational hypertension that does not resolve after birth should be reclassified as chronic hypertension.

(4) Pre‐eclampsia superimposed on chronic hypertension

Women with chronic hypertension may then develop pre‐eclampsia. This is diagnosed where there is new onset of proteinuria, or sudden worsening of either hypertension or proteinuria, or development of other signs and symptoms of pre‐eclampsia after 20 weeks of gestation.

Pathophysiology

While the underlying cause of this syndrome remains unknown, it is thought perhaps to be associated with endothelial damage, increased permeability of the capillaries, an increased after‐load of the heart due to systemic vascular resistance and increased left ventricular work index (Mabie 2010). These changes may result in acute renal failure and pulmonary oedema, the consequences of which can be quite devastating, with the patient often requiring invasive or non‐invasive ventilation support and dialysis.

The haemodynamic changes found to occur with hypertension in pregnancy are:

• variable cardiac output (increase in cardiac output was reported in some early studies (Hilary 1951), subsequent reports showed that women with preeclampsia had raised cardiac outputs prior to the diagnosis and reduced cardiac output during clinical stages of preeclampsia (Bosio 1999));

• mean arterial pressure elevation, normal systemic vascular resistance (SVR) in the early stages and elevated SVR in the late stages that may be consistent with early hyperdynamic changes without vasospasm in early pregnancy, but later vasospastic changes in late pregnancy;

• central venous pressure is usually low to normal and does not correlate well with pulmonary capillary wedge pressure (PCWP);

• pulmonary hypertension and pulmonary vascular resistance are not present, but low pulmonary artery pressure may occur in the presence of hypovolaemia; these findings suggest that the pulmonary vasculature may not be involved in the vasospastic process;

• PCWP is variable (usually low in untreated patients and normal or raised in women receiving antihypertensive medications (Sibai 1991));

• oliguria may not be a reflection of volume depletion;

• ventricular function is usually hyperdynamic, but may be depressed in the presence of marked elevation in systemic vascular resistance;

• colloid oncotic pressure is usually low.

For a more detailed review of the aetiology and pathophysiology of pre‐eclampsia see Meher 2005.

Although the outcome following pre‐eclampsia or eclampsia is good for most women, these conditions remain major causes of maternal mortality. Over half a million women die each year from pregnancy‐related causes, and 99% of these deaths occur in the developing world WHO 2005. In poorer countries, maternal mortality is still 100 to 200 times higher than in Europe and North America. Women in industrialised countries have an average lifetime risk (calculated as the average number of pregnancies multiplied by the risk associated with each pregnancy) of dying from pregnancy‐related causes of between one in 30,000, whereas women in low‐income countries have a risk of one in six Ronsmans 2006. There is no other public health statistic for which the disparity between rich and poor countries is so wide. An estimated 10% to 15% of maternal deaths in developing countries are associated with pre‐eclampsia or eclampsia (Duley 1992; Khan 2006), as are 13% to 15% of the direct obstetric deaths in the UK (Lewis 2007) and USA (ACOG 1996). Perinatal mortality is also increased following pre‐eclampsia (Ananth 1995).

Description of the intervention

The pulmonary artery catheter is inserted using the Saldinger method into the right heart. The initial access point is via either the internal jugular vein or the subclavian vein. The catheter passes into the superior vena cava and into the right ventricle where it is floated into the outflow tract of the right ventricle and comes to rest in the pulmonary arteries (Swan 1970).

Complications of this procedure include pneumothorax and insertion site infection (1% to 5%) which may not be directly related to the pulmonary artery catheter itself but rather to central ine monitoring and also less common adverse events including thromboembolism, air embolism, sepsis, pulmonary infarction, direct trauma and catheter entrapment. These less common events occur in less than one per cent. More common is a transient non‐lethal arrhythmia which can happen in 3% to 50% of patients (Clark 2010).

How the intervention might work

It is thought that a pulmonary artery catheter, being in a very close proximity with the left side of the heart, can be used to closely approximate the filling pressures of the left heart itself via the use of PCWP. As such, the pulmonary artery catheter is a better instrument for measuring the fluid status of a patient than a central line, which can only measure right heart filling pressures and has poor correlation with PCWP. Some centres have advocated for its use in women with pre‐eclampsia to better assess their fluid status, and thus better manage complications such as pulmonary oedema and renal dysfunction.

Why it is important to do this review

The management of fluid balance is of vital importance in pre‐eclampsia, given its risk of pulmonary oedema, as well as associated complications such as respiratory failure, renal dysfunction, and the need for mechanical (both invasive and non‐invasive) ventilation. The haemodynamics of the pre‐eclamptic patient is highly variable with treatment of the condition blurring the haemodynamics which may mean that closer monitoring of this state is warranted (Visser 1991).

The current indications for the use of pulmonary artery catheter in pregnancy related hypertension are (Clark 2010):

• complications related to central volume status;

• pulmonary oedema of uncertain aetiology;

• pulmonary oedema unresponsive to conventional therapy;

• persistent oliguria despite aggressive volume expansion;

• induction of conduction anaesthesia in haemodynamically unstable patients;

• medical complications that would otherwise require invasive monitoring.

Pulmonary oedema

Generally, it is noted that older patients, multigravidas and those patients with underlying chronic hypertension are more likely to develop pulmonary oedema associated with pre‐eclampsia. The reported incidence is around 2.9% Sibai 1987 with 70% of these developing in the postpartum period.

The reduction of colloid osmotic pressure (COP), alteration of capillary membrane permeability and elevated pulmonary vascular hydrostatic pressure may lead to extravasation of fluid into the pulmonary interstitium and alveolar spaces. It is thought that although the causes of pulmonary oedema in pre‐eclampsia are multifactorial, the non‐hydrostatic elements play a more important role in pre‐eclampsia. A pulmonary artery catheter may be useful in distinguishing between fluid overload, left ventricular dysfunction and non‐hydrostatic pulmonary oedema. The catheter will also be useful in determining the degree of diuresis a patient requires Pulmonary Artery Catheter Consensus Statement 1997.

Ultimately, some patients with pulmonary oedema require mechanical ventilation.

Renal complications

Acute renal failure in pre‐eclamptic pregnancies is relatively uncommon but devastating when it does occur, with high maternal and perinatal complications. Renal biopsies of pre‐eclamptic women often show a distinctive glomerular capillary endothelial cell change called glomerular endotheliosis and damage to the glomerular membranes. Acute renal failure occurs in pre‐eclampsia due to acute tubular necrosis, but may be secondary to bilaterally cortical necrosis. Precipitating factors include: abruption, coagulopathy, haemorrhage and severe hypotension.

Oliguria is much more common as the main manifestation of renal dysfunction in pre‐eclampsia. Oliguria is defined as urinary output less than 20 to 30 mL/hr over two consecutive hours, or less than 500 mL in 24 hours. This often is associated with a rise in serum creatinine and blood urea and a fall in creatinine clearance. Significant albumin/creatinine ratio disruptions also occur.

There are generally three groups of oliguria in pre‐eclamptic patients. The first group are found to have low PCWP; hyperdynamic left ventricular function and mild to moderately increased SVR. These patients respond to further volume replacement and the oliguria is felt to be due to intravascular volume depletion.

The second group of oliguric patients have normal or increased PCWP, normal cardiac output (CO) and normal SVR accompanied by intense uro‐concentration. It is thought that the pathological basis in this case is intrinsic renal artery spasm out of proportion to the degree of generalised systemic vasospasm. Low‐dose vasodilators such as dopamine have been described to raise the urine output in the group of pre‐eclamptic women.

The final group of oliguric patients have markedly elevated PCWP and SVR with depressed ventricular function. In many cases, this is accompanied by incipient pulmonary oedema with fluid accumulation in the pulmonary interstitium. This is generally thought to be due to intense systemic vasospasm and the management would be fluid restriction and aggressive after‐load reduction.

The insertion of a pulmonary artery catheter in the case of oliguria would be very beneficial as these three distinct causes of oliguria are clinically indistinguishable from each other and yet require very different forms of management Deering 2010.

However, the insertion of a pulmonary artery catheter requires a high level of technical expertise and is not without severe complications. These include cardiac arrhythmias, pneumothorax, haemothorax, injury to vascular and neurologic structures, pulmonary infarction, and pulmonary haemorrhage and infection. Later complications include balloon rupture, thromboembolism, catheter knotting, pulmonary valve rupture and catheter migration into the pericardial and pleural spaces, with subsequent cardiac tamponade and hydrothorax (see above). In addition to this, use of the pulmonary artery catheter and interpretation of its data require significant expertise (Clark 2010). Given these factors, there has been no review to date which formally assesses all the evidence surrounding the use of pulmonary artery catheters in women with severe pre‐eclampsia. It is this gap which this review will attempt to fill.

Objectives

To determine the safety and efficacy of the pulmonary flow catheter in women with severe pre‐eclampsia in preventing renal failure and pulmonary oedema. To determine the safety and efficacy of the pulmonary flow catheter in women with severe pre‐eclampsia in the management of renal failure, pulmonary oedema, or both.

Methods

Criteria for considering studies for this review

Types of studies

We did not identify any relevant studies. We planned to include adequately randomised trials evaluating use of pulmonary artery catheterisation in the management of pre‐eclamptic and eclamptic antepartum, intrapartum and postpartum women. We did not intend to include cluster‐randomised trials. We planned to exclude studies with a quasi‐random design, studies with a cross‐over design, as well as abstract‐only studies.

Types of participants

We planned to include trials of women with pre‐eclampsia regardless of gestational age at trial entry.

Types of interventions

We intended to consider trials that included pulmonary artery catheterisation of pre‐eclamptic or eclamptic women with or without pulmonary oedema and renal failure as an intervention group compared with a control group of pre‐eclamptic or eclamptic women with or without pulmonary oedema and renal failure who did not receive pulmonary artery catheterisation.

Types of outcome measures

The outcomes of interest are listed below. In future updates of this review, if we identify relevant trials and an important outcome is not reported, whenever possible, we will contact the authors. To avoid losing valuable data, we will also include trials that use acceptable variations of the definitions specified below, as will those that do not state their definitions. We may add additional outcomes for trials where the intervention being evaluated has specific adverse effects, and we will discuss these and justify their inclusion in the review.

Primary outcomes

Maternal

• Pulmonary oedema

• Renal failure

Secondary outcomes

Maternal

• Complications of insertion of pulmonary catheter (bleeding/haematoma, infection, failure to insert, damage to heart or great vessels or internal organs, thrombosis)

• Systemic effects of pre‐eclampsia, e.g. hepatic failure, coagulopathy and disseminated intravascular coagulation (DIC), placental abruption, neurological symptoms

• Maternal death

• Maternal intensive care length of stay

• Requirement of invasive or non invasive ventilation

• Requirement of non‐invasive ventilation (continuous positive airway pressure, bilevel positive airway pressure,)

• Haemodialysis

Fetal

• Perinatal mortality

• Prematurity (less than 37 weeks' gestation)

• Admission to neonatal intensive care unit

• Neonatal complications (acute respiratory distress syndrome, necrotising enterocolitis, cerebral haemorrhage, need for mechanical ventilation)

Search methods for identification of studies

Electronic searches

We contacted the Trials Search Co‐ordinator to search the Cochrane Pregnancy and Childbirth Group’s Trials Register (30 April 2012).

The Cochrane Pregnancy and Childbirth Group’s Trials Register is maintained by the Trials Search Co‐ordinator and contains trials identified from:

1. monthly searches of the Cochrane Central Register of Controlled Trials (CENTRAL);

2. weekly searches of MEDLINE;

3. weekly searches of EMBASE;

4. handsearches of 30 journals and the proceedings of major conferences;

5. weekly current awareness alerts for a further 44 journals plus monthly BioMed Central email alerts.

Details of the search strategies for CENTRAL, MEDLINE and EMBASE, the list of handsearched journals and conference proceedings, and the list of journals reviewed via the current awareness service can be found in the ‘Specialized Register’ section within the editorial information about the Cochrane Pregnancy and Childbirth Group.

Trials identified through the searching activities described above are each assigned to a review topic (or topics). The Trials Search Co‐ordinator searches the register for each review using the topic list rather than keywords. 

Searching other resources

For future updates of this review, we will contact authors of the trials presented only in abstract form to get necessary details and include these trials if they are considered to be of adequate quality.

We will not apply any language restrictions.

Data collection and analysis

This review did not identify any trials for inclusion. Future updates of this review will use the following methods for data collection and analysis.

Selection of studies

Two review authors will independently assess for inclusion all the potential studies we identify as a result of the search strategy. We will resolve any disagreement through discussion.

Data extraction and management

We will design a form to extract data. For eligible studies, two review authors will extract the data using the agreed form. We will resolve discrepancies through discussion or, if required, we will consult a third person. Data will be entered into Review Manager software (RevMan 2011) and checked for accuracy.

When information regarding any of the above is unclear, we will attempt to contact authors of the original reports to provide further details.

Assessment of risk of bias in included studies

Two review authors will independently assess risk of bias for each study using the criteria outlined in the Cochrane Handbook for Systematic Reviews of Interventions (Higgins 2011). Any disagreement will be resolved by discussion or by involving a third assessor.

(1) Random sequence generation (checking for possible selection bias)

We will describe for each included study the method used to generate the allocation sequence in sufficient detail to allow an assessment of whether it should produce comparable groups.

We will assess the method as:

• low risk of bias (any truly random process, e.g. random number table; computer random number generator);

• high risk of bias (any non‐random process, e.g. odd or even date of birth; hospital or clinic record number);

• unclear risk of bias.

 (2) Allocation concealment (checking for possible selection bias)

We will describe for each included study the method used to conceal allocation to interventions prior to assignment and will assess whether intervention allocation could have been foreseen in advance of, or during recruitment, or changed after assignment.

We will assess the methods as:

• low risk of bias (e.g. telephone or central randomisation; consecutively numbered sealed opaque envelopes);

• high risk of bias (open random allocation; unsealed or non‐opaque envelopes, alternation; date of birth);

• unclear risk of bias.

(3.1) Blinding of participants and personnel (checking for possible performance bias)

We will describe for each included study the methods used, if any, to blind study participants and personnel from knowledge of which intervention a participant received. We will consider that studies are at low risk of bias if they were blinded, or if we judge that the lack of blinding would be unlikely to affect results. We will assess blinding separately for different outcomes or classes of outcomes.

We will assess the methods as:

• low, high or unclear risk of bias for participants;

• low, high or unclear risk of bias for personnel.

(3.2) Blinding of outcome assessment (checking for possible detection bias)

We will describe for each included study the methods used, if any, to blind outcome assessors from knowledge of which intervention a participant received. We will assess blinding separately for different outcomes or classes of outcomes.

We will assess methods used to blind outcome assessment as:

• low, high or unclear risk of bias.

(4) Incomplete outcome data (checking for possible attrition bias due to the amount, nature and handling of incomplete outcome data)

We will describe for each included study, and for each outcome or class of outcomes, the completeness of data including attrition and exclusions from the analysis. We will state whether attrition and exclusions were reported and the numbers included in the analysis at each stage (compared with the total randomised participants), reasons for attrition or exclusion where reported, and whether missing data were balanced across groups or were related to outcomes. Where sufficient information is reported, or can be supplied by the trial authors, we will re‐include missing data in the analyses which we undertake.

We will assess methods as:

• low risk of bias (e.g. no missing outcome data; missing outcome data balanced across groups);

• high risk of bias (e.g. numbers or reasons for missing data imbalanced across groups; ‘as treated’ analysis done with substantial departure of intervention received from that assigned at randomisation);

• unclear risk of bias.

(5) Selective reporting bias

We will describe for each included study how we investigated the possibility of selective outcome reporting bias and what we found.

We will assess the methods as:

• low risk of bias (where it is clear that all of the study’s pre‐specified outcomes and all expected outcomes of interest to the review have been reported);

• high risk of bias (where not all the study’s pre‐specified outcomes have been reported; one or more reported primary outcomes were not prespecified; outcomes of interest are reported incompletely and so cannot be used; study fails to include results of a key outcome that would have been expected to have been reported);

• unclear risk of bias.

(6) Other bias (checking for bias due to problems not covered by (1) to (5) above)

We will describe for each included study any important concerns we have about other possible sources of bias. In particular we will look at the number of the participants in each of the studies in the review and assess for risk of bias.

We will assess whether each study was free of other problems that could put it at risk of bias:

• low risk of other bias;

• high risk of other bias;

• unclear whether there is risk of other bias.

(7) Overall risk of bias

We will make explicit judgements about whether studies are at high risk of bias, according to the criteria given in the Handbook (Higgins 2011). With reference to (1) to (6) above, we will assess the likely magnitude and direction of the bias and whether we consider it is likely to impact on the findings. We will explore the impact of the level of bias through undertaking sensitivity analyses ‐ seeSensitivity analysis. 

Measures of treatment effect

Dichotomous data

For dichotomous data, we will present results as summary risk ratio with 95% confidence intervals. 

Continuous data

For continuous data, we will use the mean difference if outcomes are measured in the same way between trials. We will use the standardised mean difference to combine trials that measure the same outcome, but use different methods.  

Unit of analysis issues

Cluster‐randomised trials

Cluster‐randomised trials will not be included.

Cross‐over trials

Cross‐over trials are irrelevant for this intervention, and, therefore we will not include them.

Multi‐armed trials

When analysing multi‐armed trials, we will combine all relevant experimental intervention groups of the study into a single group and all relevant control intervention groups into a single control group. If the authors have considered one of the arms irrelevant, we will exclude it from analysis.

Dealing with missing data

For included studies, we will note levels of attrition. We will explore the impact of including studies with high levels of missing data in the overall assessment of treatment effect by using sensitivity analysis.

For all outcomes, we will carry out analyses, as far as possible, on an intention‐to‐treat basis, i.e. we will attempt to include all participants randomised to each group in the analyses, and all participants will be analysed in the group to which they were allocated, regardless of whether or not they received the allocated intervention. The denominator for each outcome in each trial will be the number randomised minus any participants whose outcomes are known to be missing.

Assessment of heterogeneity

We will assess statistical heterogeneity in each meta‐analysis using the T², I² and Chi² statistics. We will regard heterogeneity as substantial if I² is greater than 30% and either T² is greater than zero, or there is a low P value (less than 0.10) in the Chi² test for heterogeneity. 

Assessment of reporting biases

If there are 10 or more studies in the meta‐analysis we will investigate reporting biases (such as publication bias) using funnel plots. We will assess funnel plot asymmetry visually, and use formal tests for funnel plot asymmetry. For continuous outcomes, we will use the test proposed by Egger 1997, and for dichotomous outcomes we will use the test proposed by Harbord 2006. If asymmetry is detected in any of these tests or is suggested by a visual assessment, we will perform exploratory analyses to investigate it.

Data synthesis

We will carry out statistical analysis using the Review Manager software (RevMan 2011). We will use fixed‐effect meta‐analysis for combining data where it is reasonable to assume that studies are estimating the same underlying treatment effect: i.e. where trials are examining the same intervention, and the trials’ populations and methods are judged sufficiently similar. If there is clinical heterogeneity sufficient to expect that the underlying treatment effects differ between trials, or if substantial statistical heterogeneity is detected, we will use random‐effects meta‐analysis to produce an overall summary if an average treatment effect across trials is considered clinically meaningful. The random‐effects summary will be treated as the average range of possible treatment effects and we will discuss the clinical implications of treatment effects differing between trials. If the average treatment effect is not clinically meaningful, we will not combine trials.

If we use random‐effects analyses, the results will be presented as the average treatment effect with its 95% confidence interval, and the estimates of  T² and I².

Subgroup analysis and investigation of heterogeneity

If we identify substantial heterogeneity, we will investigate it using subgroup analyses and sensitivity analyses. We will consider whether an overall summary is meaningful, and if it is, use random‐effects analysis to produce it.

We plan to carry out the following subgroup analyses.

1. Women with severe pre‐eclampsia without pulmonary oedema or renal failure.

2. Women with severe pre‐eclampsia with either pulmonary oedema, or renal failure, or both.

We will use the following outcomes in the subgroup analysis.

1. Complications of insertion of pulmonary catheter (bleeding/haematoma, infection, failure to insert, damage to heart or great vessels or internal organs, thrombosis).

2. Systemic effects of pre‐eclampsia, e.g. hepatic failure, coagulopathy and DIC, placental abruption, neurological symptoms, pulmonary oedema and renal failure.

For fixed‐effect inverse variance meta‐analyses, we will assess differences between subgroups by interaction tests. For random‐effects and fixed‐effect meta‐analyses using methods other than inverse variance, we will assess differences between subgroups by inspection of the subgroups’ confidence intervals; non‐overlapping confidence intervals indicate a statistically significant difference in treatment effect between the subgroups.

Sensitivity analysis

We will perform sensitivity analysis for primary outcomes if we identify substantial heterogeneity in the included studies.

Results

Description of studies

There were no randomised controlled trials identified from the search strategy.

Results of the search

The search of the Cochrane Pregnancy and Childbirth Group's Trials Register found no relevant trial reports.

Risk of bias in included studies

There were no randomised controlled trials identified from the search strategy.

Effects of interventions

There were no randomised controlled trials identified from the search strategy.

Discussion

The inability of the authors to find adequate randomised data fitting in with the search strategy of the review does not negate the validity of the issues raised by this review, namely that of managing pulmonary oedema and of fluid management in pre‐eclampsia.

The clinical incidence of pulmonary oedema may be low at 2.9% (Sibai 1987) but its true clinical relevance may be vastly underestimated. Pregnancy‐related hypertension is ranked only second to HIV/AIDS as a source of maternal death and accounts for around 15% of all deaths in South Africa (Moodley 2010) and is a leading cause of death in other developing countries (Khan 2006).

In this category, while cerebrovascular haemorrhage is the main cause of death at 45%, hypovolaemic shock, respiratory failure, cardiac failure and renal failure combined are involved in 60% of deaths related to pregnancy‐induced hypertension. The final pathogenesis for respiratory, cardiac and renal failure in the setting of pre‐eclampsia is pulmonary oedema or pulmonary oedema via fluid overload (Benedetti 1985). Hence, the management of pulmonary oedema is of vital importance.

In addition, data published by Vikse and co‐authors (Vikse 2008), show a significant link between women with pre‐eclampsia and end stage renal failure. This would suggest that the renal dysfunction in pre‐eclampsia could be more than just acute tubular necrosis and involve a degree of renal cortical necrosis. This would counteract the 'run them dry' management in preventing pulmonary oedema as it would argue for adequate perfusion of the kidneys.

These two conflicting point of views would mean that achieving a balance in fluid management in pre‐eclampsia, especially in places where the severest form of this disease has its highest prevalence, is difficult. An aggressive approach can push a woman into pulmonary oedema while being too conservative could result in severe long‐term complications. A point can be made that invasive monitoring using pulmonary capillary wedge pressure (PCWP) in order to optimise fluid management in this group of patients is warranted (ACOG 2002).

However, it is recognised, despite the relevance and complexity of the issues raised in this review, that the skill involved in pulmonary artery catheterisation and subsequent monitoring of PCWP, the risks and indeed costs of the procedure would make large‐scale randomised data almost impossible to source. The complexity of cases needing pulmonary artery catheters will almost certainly make randomisation impossible. It is also noted that routine pulmonary artery catheterisation, even in the non‐pregnant population, is dropping. A joint statement however, issued by the American College of Thoracic Surgeons, Critical Care Medicine and Critical Care Nursing have implied that pulmonary artery catheters still have a role to play but their practice is to be individualised rather than routine (Pulmonary Artery Catheter Consensus Statement 1997).

Perhaps the only practical way of examining the role of pulmonary artery catheterisation in pregnancy may be to use case series data or data obtained from a registry. However, such data's ability to form sound generalised conclusions, unless they are large in nature would be very limited.

Authors' conclusions

Implications for practice.

There are obvious risks and potential benefits, as outlined above, in using pulmonary artery catheterisation. There is insufficient level 1 or 2 evidence to support using pulmonary artery catheters over traditional non‐invasive methods of fluid balance management or vice versa.

Implications for research.

The importance of fluid management in pre‐eclampsia cannot be doubted, with both short‐term and long‐term implications for morbidity and mortality. The complexity of this issue would suggest that using pulmonary capillary wedge pressure as a form of measuring fluid load and in balancing the issues of adequate renal perfusion and prevention of pulmonary to be potentially useful.

Ideally, there needs to be randomised controlled trials to both demonstrate efficacy and associated morbidity with the use of pulmonary artery catheters as an aid in managing fluid balance in pre‐eclampsia. Yet the authors are realistic that randomised controlled trials of such a nature, due to many issues including associated complications of the procedure, difficulty and complexity, and cost, may make this impossible. Instead, evidence for use may become reliant on smaller registers or case series. Without large numbers, it would be difficult to make generalisations from any such studies.

Feedback

Dennis, August 2012

Summary

I read this Cochrane Review with interest. The review authors conclude by calling for further randomised controlled trials (RCTs) evaluating pulmonary artery catheters, an invasive procedure, to monitor fluid balance in pre‐eclampsia.  I have concerns about this recommendation. 

Pulmonary artery catheters are just one of a range of diagnostic modalities that may be used for women with pre‐eclampsia. Historically pulmonary artery catheters were more widely utilised. In recent times, however, due to their known complications^1,2 and with improved care for women with pre‐eclampsia, they are rarely used^3‐6. As a result of this shift in practice, clinicians and trainees are becoming less familiar with their use. 

One emerging non‐invasive technology is transthoracic echocardiography (TTE). It is a precise device that has been validated in pregnancy ^{7, 8}. It provides accurate information about systolic and diastolic function. The review authors correctly point out that prevention of acute pulmonary oedema is important in women with pre‐eclampsia. To this end, quantification of diastolic function is important, because hypertensive acute pulmonary oedema in pregnant women is due to diastolic heart failure⁹. Measurement of diastolic function as well as ejection fraction, contractility and left ventricular end diastolic volumes can be done with TTE. As can direct observation of the structure of the heart, thereby enabling left ventricular wall thickness, the presence of pericardial effusions, and right heart function to be assessed. TTE is applicable in women with pre‐eclampsia as well as obese pregnant women and importantly, from a consumer point of view, is acceptable to pregnant women^10‐12.

Pulmonary artery catheters may provide additional information during birth or an acute life‐threatening complication for the occasional woman with pre‐eclampsia superimposed on pre‐existing underlying heart disease (i.e. valvular disease, congenital heart disease), or for critically ill women with pre‐eclampsia and diastolic and/or systolic heart failure. In these uncommon situations of complex pathophysiology and pharmacology, the risks of a pulmonary artery catheter may be outweighed by the clinical benefit of continuous numerical information, and it can be used in addition to less invasive devices. In the context of an RCT, however, this clinical heterogeneity may lead to significant confounding even if the necessarily large sample size was achieved. 
 
 Given the known serious risks of pulmonary artery catheters, their rare use for women with pre‐eclampsia, and the availability of validated, accurate and precise alternative diagnostic tools, I do not think that the recommendation of further RCTs evaluating pulmonary artery catheters is appropriate. In addition, in the age of echocardiography and other less invasive, information rich technologies, I think it may also be unethical.

References

1. Harvey S, Young D, Brampton W, Cooper A, Doig GS, Sibbald W, Rowan K. Pulmonary artery catheters for adult patients in intensive care. Cochrane Database of Systematic Reviews 2006, Issue 3. Art. No.: CD003408. DOI: 10.1002/14651858.CD003408.pub2. 
 2. Cowie BS. Does the pulmonary artery catheter still have a role in the perioperative period? Anaesth Intensive Care 2011;39:345‐55. 
 3. Cantwell R, Clutton‐Brock T, Cooper G, et al. Saving Mothers' Lives: Reviewing maternal deaths to make motherhood safer: 2006‐2008. The Eighth Report of the Confidential Enquiries into Maternal Deaths in the United Kingdom. BJOG  2011;118 Suppl 1:1‐203. 
 4. Armstrong S, Fernando R, Columb M. Minimally‐ and non‐invasive assessment of maternal cardiac output: go with the flow! International Journal of Obstetric Anesthesia 2011;20:330‐40. 
 5. Dyer RA, Piercy JL, Reed AR, et al. Comparison between pulse waveform analysis and thermodilution cardiac output determination in patients with severe pre‐eclampsia. British Journal of Anaesthesia 2011;106:77‐81. 
 6. Langesaeter E, Rosseland LA, Stubhaug A. Haemodynamic effects of oxytocin in women with severe preeclampsia. International Journal of Obstetric Anesthesia 2011;20(1):26‐9. 
 7. Easterling TR, Watts DH, Schmucker BC, Benedetti TJ. Measurement of cardiac output during pregnancy: validation of Doppler technique and clinical observations in preeclampsia. Obstetrics and Gynecology 1987;69:845‐50. 
 8. Robson SC, Dunlop W, Moore M, Hunter S. Combined Doppler and echocardiographic measurement of cardiac output: theory and application in pregnancy. BJOG 1987;94:1014‐27. 
 9. Dennis AT, Solnordal CB. Acute pulmonary oedema in pregnant women. Anaesthesia 2012;67:646‐59. 
 10. Dennis AT, Castro JM, Ong M, Carr C. Haemodynamics in obese pregnant women. International Journal of Obstetric Anesthesia 2012;21(2):129‐34. 
 11. Dennis A, Arhanghelschi I, Simmons S, Royse C. Prospective observational study of serial cardiac output by transthoracic echocardiography in healthy pregnant women undergoing elective caesarean delivery. International Journal of Obstetric Anesthesia 2010;19:142‐8. 
 12. Dennis AT, Castro J, Carr C, Simmons S, Permezel M, Royse C. Haemodynamics in women with untreated pre‐eclampsia* DOI 10.1111/j.1365‐2044.2012.07193.x. Anaesthesia 2012.

[Comment submitted by Alicia Dennis, August 2012]

Reply

A reply from the authors will be published as soon as it is available.

What's new

Date	Event	Description
2 October 2012	Feedback has been incorporated	Feedback from Alicia Dennis added ‐ see Feedback 1.

Contributions of authors

Both authors, Ying Li and Natalia Novikova, designed and collaborated in writing the protocol. and the review. Ying Li is guarantor for the review.

Declarations of interest

None known.

Edited (no change to conclusions), comment added to review